research articles in antibiotics

A review of current antibiotic resistance and promising antibiotics with novel modes of action to combat antibiotic resistance

• Mini Review
• Published: 20 October 2023
• Volume 205 , article number  356 , ( 2023 )

Cite this article

• Lei Chen 1 , 2 ,
• Suresh Kumar 3 &
• Hongyan Wu 1  

1592 Accesses

4 Citations

1 Altmetric

Explore all metrics

The emergence and transmission of antibiotic resistance is a global public health crisis with significant burden on healthcare systems, resulting in high mortality and economic costs. In 2019, almost five million deaths were associated with drug-resistant infections, and if left unchecked, the global economy could lose $100 trillion by 2050. To effectively combat this crisis, it is essential for all countries to understand the current situation of antibiotic resistance. In this review, we examine the current driving factors leading to the crisis, impact of critical superbugs in three regions, and identify novel mechanisms of antibiotic resistance. It is crucial to monitor the phenotypic characteristics of drug-resistant pathogens and describe the mechanisms involved in preventing the emergence of cross-resistance to novel antimicrobials. Additionally, maintaining an active pipeline of new antibiotics is essential for fighting against diverse antibiotic-resistant pathogens. Developing antibacterial agents with novel mechanisms of action is a promising way to combat increasing antibiotic-resistant pathogens.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price includes VAT (Russian Federation)

Instant access to the full article PDF.

Rent this article via DeepDyve

Institutional subscriptions

Similar content being viewed by others

Ceftazidime-avibactam combination therapy versus monotherapy for treating carbapenem-resistant gram-negative infection: a systemic review and meta-analysis

Antimicrobial Resistance in Bacteria: Mechanisms, Evolution, and Persistence

History of Antibiotics Research

Data availability.

Not applicable.

Al-Tawfiq JA, Momattin H, Al-Ali AY et al (2022) Antibiotics in the pipeline: a literature review (2017–2020). Infection 50:553–564. https://doi.org/10.1007/s15010-021-01709-3

Article   PubMed   Google Scholar  

Andrei S, Droc G, Stefan G (2019) FDA approved antibacterial drugs: 2018–2019. Discoveries 7:e102. https://doi.org/10.15190/d.2019.15

Article   PubMed   PubMed Central   Google Scholar  

Asokan G, Ramadhan T, Ahmed E, Sanad H (2019) WHO global priority pathogens list: a bibliometric analysis of Medline-Pubmed for knowledge mobilization to infection prevention and control practices in Bahrain. Oman Med J 34:184–193. https://doi.org/10.5001/omj.2019.37

Article   CAS   PubMed   PubMed Central   Google Scholar  

Ayikpoe RS, Shi C, Battiste AJ et al (2022) A scalable platform to discover antimicrobials of ribosomal origin. Nat Commun 13:6135. https://doi.org/10.1038/s41467-022-33890-w

Biswas S (2023) Synthesis of a novel lantibiotic using mutacin II biosynthesis apparatus. Microbiol Spectr. https://doi.org/10.1128/spectrum.03030-22

Butler MS, Gigante V, Sati H et al (2022) Analysis of the clinical pipeline of treatments for drug-resistant bacterial infections: despite progress, more action is needed. Antimicrob Agents Chemother. https://doi.org/10.1128/aac.01991-21

Cavaco M, Castanho MARB, Neves V (2022) The use of antibody-antibiotic conjugates to fight bacterial infections. Front Microbiol. https://doi.org/10.3389/fmicb.2022.835677

CDC (2021) Carbapenem-resistant Acinetobacter baumannii (CRAB): an urgent public health threat in United States healthcare facilities. https://arpsp.cdc.gov/story/cra-urgent-public-health-threat . Accessed 21 Sep 2023

Centers for Disease Control and Prevention (2019) 2019 AR threats report. https://www.cdc.gov/drugresistance/biggest-threats.html . Accessed 14 Sep 2023

Centers for Disease Control and Prevention (2020) About antibiotic resistance. https://www.cdc.gov/drugresistance/about.html . Accessed 25 Nov 2021

Centers for Disease Control and Prevention (2022) Carbapenem-resistant Enterobacterales (CRE) and Pseudomonas aeruginosa (CRPA) carrying multiple targeted carbapenemase genes. https://arpsp.cdc.gov/profile/multi-mechanism/2021 . Accessed 21 Sep 2023

Chen S, Liu D, Zhang Q, Guo P, Ding S, Shen J, Zhu K, Lin W (2021) A marine antibiotic kills multidrug-resistant bacteria without detectable high-level resistance. ACS Infect Dis 7:884–893. https://doi.org/10.1021/acsinfecdis.0c00913

Article   CAS   PubMed   Google Scholar  

Dai C, Zhou M, Jiang W et al (2020) Breaking or following the membrane-targeting mechanism: exploring the antibacterial mechanism of host defense peptide mimicking poly(2-oxazoline)s. J Mater Sci Technol 59:220–226. https://doi.org/10.1016/j.jmst.2020.06.006

Article   CAS   Google Scholar  

de Kraker MEA, Stewardson AJ, Harbarth S (2016) Will 10 million people die a year due to antimicrobial resistance by 2050? PLoS Med 13:e1002184. https://doi.org/10.1371/journal.pmed.1002184

FDA (2019) FDA approves new antibacterial drug to treat complicated urinary tract infections as part of ongoing efforts to address antimicrobial resistance. https://www.fda.gov/news-events/press-announcements/fda-approves-new-antibacterial-drug-treat-complicated-urinary-tract-infections-part-ongoing-efforts . Accessed 24 Sep 2023

Forde BM, Henderson A, Playford EG et al (2021) Fatal respiratory diphtheria caused by β-lactam–resistant Corynebacterium diphtheriae . Clin Infect Dis 73:e4531–e4538. https://doi.org/10.1093/cid/ciaa1147

Fraile-Ribot PA, Cabot G, Mulet X et al (2018) Mechanisms leading to in vivo ceftolozane/tazobactam resistance development during the treatment of infections caused by MDR Pseudomonas aeruginosa . J Antimicrob Chemother 73:658–663. https://doi.org/10.1093/jac/dkx424

Gaibani P, Giani T, Bovo F et al (2022) Resistance to ceftazidime/avibactam, meropenem/vaborbactam and imipenem/relebactam in gram-negative MDR bacilli: molecular mechanisms and susceptibility testing. Antibiotics 11:628. https://doi.org/10.3390/antibiotics11050628

Gil-Gil T, Corona F, Martínez JL, Bernardini A (2020) The inactivation of enzymes belonging to the central carbon metabolism is a novel mechanism of developing antibiotic resistance. mSystems. https://doi.org/10.1128/mSystems.00282-20

Golikova MV, Strukova EN, Portnoy YA, Dovzhenko SA, Kobrin MB, Zinner SH, Firsov AA (2019) A novel parameter to predict the effects of antibiotic combinations on the development of Staphylococcus aureus resistance: in vitro model studies at subtherapeutic daptomycin and rifampicin exposures. J Chemother 31:320–328. https://doi.org/10.1080/1120009X.2019.1640924

Goryluk-Salmonowicz A, Popowska M (2022) Factors promoting and limiting antimicrobial resistance in the environment—existing knowledge gaps. Front Microbiol. https://doi.org/10.3389/fmicb.2022.992268

Guo Y, Gao J, Wang Z, Cui Y, Li Z, Wu Z, Zhao Y, Li D, Dai H (2022) The fate and behavior mechanism of antibiotic resistance genes and microbial communities in flocs, aerobic granular and biofilm sludge under chloroxylenol pressure. J Hazard Mater 438:129465. https://doi.org/10.1016/j.jhazmat.2022.129465

Hashemi P, Mahmoodi S, Ghasemian A (2023) An updated review on oral protein-based antigen vaccines efficiency and delivery approaches: a special attention to infectious diseases. Arch Microbiol 205:289. https://doi.org/10.1007/s00203-023-03629-2

Huang D, Pachuda N, Sauer JM, Dobbins D, Steckbeck J (2021) The engineered antibiotic peptide PLG0206 eliminates biofilms and is a potential treatment for periprosthetic joint infections. Antibiotics 11:41. https://doi.org/10.3390/antibiotics11010041

Huemer M, Shambat SM, Brugger SD, Zinkernagel AS (2020) Antibiotic resistance and persistence—implications for human health and treatment perspectives. EMBO Rep. https://doi.org/10.15252/embr.202051034

Hwang AY, Gums JG (2016) The emergence and evolution of antimicrobial resistance: impact on a global scale. Bioorg Med Chem 24:6440–6445. https://doi.org/10.1016/j.bmc.2016.04.027

Ivanov M, Kostić M, Stojković D, Soković M (2022) Rosmarinic acid—modes of antimicrobial and antibiofilm activities of a common plant polyphenol. S Afr J Bot 146:521–527. https://doi.org/10.1016/j.sajb.2021.11.050

Jangpromma N, Konkchaiyaphum M, Punpad A et al (2022) Rational design of RN15m4 cathelin domain-based peptides from siamese crocodile cathelicidin improves antimicrobial activity. Appl Biochem Biotechnol. https://doi.org/10.1007/s12010-022-04210-1

Jelinkova P, Mazumdar A, Sur VP et al (2019) Nanoparticle-drug conjugates treating bacterial infections. J Control Release 307:166–185. https://doi.org/10.1016/j.jconrel.2019.06.013

Jia Y, Lu H, Zhu L (2022) Molecular mechanism of antibiotic resistance induced by mono- and twin-chained quaternary ammonium compounds. Sci Total Environ 832:155090. https://doi.org/10.1016/j.scitotenv.2022.155090

Kalimuthu K, Srinivasan NR, Govindarajan G (2023) Antibiotic-peptide conjugation against multi-drug resistant pathogens: a comprehensive review for therapeutics and drug delivery strategies. Int J Pept Res Ther 29:91. https://doi.org/10.1007/s10989-023-10561-y

Kang X, Yan J, Huang F, Yang L (2019) On the mechanism of antibiotic resistance and fecal microbiota transplantation. Math Biosci Eng 16:7057–7084. https://doi.org/10.3934/mbe.2019354

Karakonstantis S, Rousaki M, Kritsotakis EI (2022) Cefiderocol: systematic review of mechanisms of resistance, heteroresistance and in vivo emergence of resistance. Antibiotics 11:723. https://doi.org/10.3390/antibiotics11060723

Kardos N (2017) Overuse of antibiotics and antibiotic resistance in medical applications featuring carbapenemase resistant enterobacteriaceae (CRE)

Kernou O-N, Azzouz Z, Madani K, Rijo P (2023) Application of rosmarinic acid with its derivatives in the treatment of microbial pathogens. Molecules 28:4243. https://doi.org/10.3390/molecules28104243

Khalid K, Poh CL (2023) The promising potential of reverse vaccinology-based next-generation vaccine development over conventional vaccines against antibiotic-resistant bacteria. Vaccines (basel) 11:1264. https://doi.org/10.3390/vaccines11071264

Kimura K (2019) Liposidomycin, the first reported nucleoside antibiotic inhibitor of peptidoglycan biosynthesis translocase I: the discovery of liposidomycin and related compounds with a perspective on their application to new antibiotics. J Antibiot (tokyo) 72:877–889. https://doi.org/10.1038/s41429-019-0241-5

Klahn P, Brönstrup M (2017) Bifunctional antimicrobial conjugates and hybrid antimicrobials. Nat Prod Rep 34:832–885. https://doi.org/10.1039/C7NP00006E

Klemm EJ, Wong VK, Dougan G (2018) Emergence of dominant multidrug-resistant bacterial clades: lessons from history and whole-genome sequencing. Proc Natl Acad Sci USA 115:12872–12877. https://doi.org/10.1073/pnas.1717162115

Koo HB, Seo J (2019) Antimicrobial peptides under clinical investigation. Pept Sci. https://doi.org/10.1002/pep2.24122

Article   Google Scholar  

Kusaka S, Yamamoto K, Shinohara M, Minato Y, Ichikawa S (2022) Design, synthesis and conformation-activity relationship analysis of LNA/BNA-type 5′- O -aminoribosyluridine as MraY inhibitors. Bioorg Med Chem 65:116744. https://doi.org/10.1016/j.bmc.2022.116744

Lee Ventola C (2015) The antibiotic resistance crisis. P&T 11:181–224. https://doi.org/10.1016/B978-1-4831-9711-1.50022-3

León-Buitimea A, Garza-Cárdenas CR, Garza-Cervantes JA et al (2020) The demand for new antibiotics: antimicrobial peptides, nanoparticles, and combinatorial therapies as future strategies in antibacterial agent design. Front Microbiol. https://doi.org/10.3389/fmicb.2020.01669

Li C, Alam K, Zhao Y et al (2021) Mining and biosynthesis of bioactive lanthipeptides from microorganisms. Front Bioeng Biotechnol. https://doi.org/10.3389/fbioe.2021.692466

Li Y, Ouyang Y, Wu H et al (2022) The discovery of 1, 3-diamino-7H-pyrrol[3, 2-f]quinazoline compounds as potent antimicrobial antifolates. Eur J Med Chem 228:113979. https://doi.org/10.1016/j.ejmech.2021.113979

Ling LL, Schneider T, Peoples AJ et al (2015) A new antibiotic kills pathogens without detectable resistance. Nature 517:455–459. https://doi.org/10.1038/nature14098

Martin JK, Sheehan JP, Bratton BP et al (2020) A dual-mechanism antibiotic kills gram-negative bacteria and avoids drug resistance. Cell 181:1518-1532.e14. https://doi.org/10.1016/j.cell.2020.05.005

Morehead MS, Scarbrough C (2018) Emergence of global antibiotic resistance. Primary Care Clin off Pract 45:467–484. https://doi.org/10.1016/j.pop.2018.05.006

Mullard A (2021) 2020 FDA drug approvals. Nat Rev Drug Discov 20:85–90

Mullard A (2022) 2021 FDA approvals. Nat Rev Drug Discov 21:83–88

Munita JM, Arias CA (2016) Mechanisms of antibiotic resistance. Virulence mechanisms of bacterial pathogens. ASM Press, Washington, DC, pp 481–511

Chapter   Google Scholar  

Nakaya T, Yabe M, Mashalidis EH et al (2022) Synthesis of macrocyclic nucleoside antibacterials and their interactions with MraY. Nat Commun 13:7575. https://doi.org/10.1038/s41467-022-35227-z

National Health Commission of China (2023) National Antibiotic Resistance Monitoring Report 2021

New drug approvals (2022) New drug approvals. https://www.drugs.com/newdrugs.html . Accessed 14 Aug 2022

Okamoto K, Ishikawa A, Okawa R et al (2022) Design, synthesis and biological evaluation of simplified analogues of MraY inhibitory natural product with rigid scaffold. Bioorg Med Chem 55:116556. https://doi.org/10.1016/j.bmc.2021.116556

Pokhrel R, Bhattarai N, Baral P et al (2022) Lipid II binding and transmembrane properties of various antimicrobial lanthipeptides. J Chem Theory Comput 18:516–525. https://doi.org/10.1021/acs.jctc.1c00666

Porras-Alcalá C, Moya-Utrera F, García-Castro M et al (2022) The development of the bengamides as new antibiotics against drug-resistant bacteria. Mar Drugs 20:373. https://doi.org/10.3390/md20060373

Qi Y, Tang X, Wei N, Pang C, Du S, Wang K (2022) Discovery, synthesis, and optimization of teixobactin, a novel antibiotic without detectable bacterial resistance. J Pept Sci. https://doi.org/10.1002/psc.3428

Romanovska A, Keil J, Tophoven J et al (2021) Conjugates of ciprofloxacin and amphiphilic block copoly(2-alkyl-2-oxazolines)s overcome efflux pumps and are active against CIP-resistant bacteria. Mol Pharm 18:3532–3543. https://doi.org/10.1021/acs.molpharmaceut.1c00430

Rončević T, Gerdol M, Mardirossian M et al (2022) Anisaxins, helical antimicrobial peptides from marine parasites, kill resistant bacteria by lipid extraction and membrane disruption. Acta Biomater 146:131–144. https://doi.org/10.1016/j.actbio.2022.04.025

Sanchari Sinha Dutta (2022) The history of antibiotics. News Medical

Shukla R, Medeiros-Silva J, Parmar A et al (2020) Mode of action of teixobactins in cellular membranes. Nat Commun 11:2848. https://doi.org/10.1038/s41467-020-16600-2

Shukla R, Lavore F, Maity S et al (2022) Teixobactin kills bacteria by a two-pronged attack on the cell envelope. Nature 608:390–396. https://doi.org/10.1038/s41586-022-05019-y

Skłodowski K, Chmielewska-Deptuła SJ, Piktel E et al (2023) Metallic nanosystems in the development of antimicrobial strategies with high antimicrobial activity and high biocompatibility. Int J Mol Sci 24:2104. https://doi.org/10.3390/ijms24032104

Stachurski O, Neubauer D, Walewska A et al (2022) Understanding the role of self-assembly and interaction with biological membranes of short cationic lipopeptides in the effective design of new antibiotics. Antibiotics 11:1491. https://doi.org/10.3390/antibiotics11111491

Tagliabue A, Rappuoli R (2018) Changing priorities in vaccinology: antibiotic resistance moving to the top. Front Immunol. https://doi.org/10.3389/fimmu.2018.01068

Talbot GH, Jezek A, Murray BE et al (2019) The infectious diseases society of America’s 10 × ’20 initiative (10 new systemic antibacterial agents US food and drug administration approved by 2020): Is 20 × ’20 a possibility? Clin Infect Dis 69:1–11. https://doi.org/10.1093/cid/ciz089

Terreni M, Taccani M, Pregnolato M (2021) New antibiotics for multidrug-resistant bacterial strains: latest research developments and future perspectives. Molecules 26:2671. https://doi.org/10.3390/molecules26092671

Tian J, Chen S, Liu F, Zhu Q, Shen J, Lin W, Zhu K (2022) Equisetin targets intracellular Staphylococcus aureus through a host acting strategy. Mar Drugs 20:656. https://doi.org/10.3390/md20110656

Udaondo Z, Matilla MA (2020) Mining for novel antibiotics in the age of antimicrobial resistance. Microb Biotechnol 13:1702–1704. https://doi.org/10.1111/1751-7915.13662

Uddin TM, Chakraborty AJ, Khusro A et al (2021) Antibiotic resistance in microbes: history, mechanisms, therapeutic strategies and future prospects. J Infect Public Health 14:1750–1766. https://doi.org/10.1016/j.jiph.2021.10.020

Waack U, Nicholson TL (2018) Subinhibitory concentrations of amoxicillin, lincomycin, and oxytetracycline commonly used to treat swine increase Streptococcus suis biofilm formation. Front Microbiol 9:1–10. https://doi.org/10.3389/fmicb.2018.02707

Wang Z, Koirala B, Hernandez Y, Zimmerman M, Brady SF (2022) Bioinformatic prospecting and synthesis of a bifunctional lipopeptide antibiotic that evades resistance. Science (1979) 376:991–996. https://doi.org/10.1126/science.abn4213

Wettstadt S (2020) Protect thy host: Pf4 phages shield Pseudomonas aeruginosa from antibiotics. Environ Microbiol 22:2461–2462. https://doi.org/10.1111/1462-2920.15046

White K, Nicoletti G, Cornell H (2021) Antibacterial profile of a microbicidal agent targeting tyrosine phosphatases and redox thiols. Novel Drug Targets Antibiot 10:1310. https://doi.org/10.3390/antibiotics10111310

WHO Library (2023) WHO Library of AMR national action plans. https://www.who.int/teams/surveillance-prevention-control-AMR/national-action-plan-monitoring-evaluation/library-of-national-action-plans . Accessed 22 Sep 2023

WHO-Policy (2011) WHO-Policy-Package-to-Combat-Antimicrobial-Resistance

Willson J (2022) Novel antibiotics from bacterial blueprints. Nat Rev Drug Discov 21:492–492. https://doi.org/10.1038/d41573-022-00102-5

Windham S, Kollef MH (2022) How to use new antibiotics in the therapy of serious multidrug resistant Gram-negative infections? Curr Opin Infect Dis 35:561–567. https://doi.org/10.1097/QCO.0000000000000858

World Health Organization (2015) Global action plan on antimicrobial resistance

World Health Organization (2020) Antibiotic resistance. https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance . Accessed 26 Oct 2022

World Health Organization (2022) Lack of innovation set to undermine antibiotic performance and health gains. https://www.who.int/news/item/22-06-2022-22-06-2022-lack-of-innovation-set-to-undermine-antibiotic-performance-and-health-gains . Accessed 22 Oct 2022

World Health Organization (2023) Health and economic impacts of antimicrobial resistance in the Western Pacific Region, 2020–2030

World Health Organization Regional Office for Europe (2023) Antimicrobial resistance surveillance in Europe (2023)

Wray R, Wang J, Blount P, Iscla I (2022) Activation of a bacterial mechanosensitive channel, MscL, underlies the membrane permeabilization of dual-targeting antibacterial compounds. Antibiotics 11:970. https://doi.org/10.3390/antibiotics11070970

Wu H, Chen H, Zhang J et al (2022) The anti-multidrug-resistant Acinetobacter baumannii study on 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline compounds. Molecules 27:8609. https://doi.org/10.3390/molecules27238609

Yamauchi R, Kawano K, Yamaoka Y, Taniguchi A, Yano Y, Takasu K, Matsuzaki K (2022) Development of antimicrobial peptide-antibiotic conjugates to improve the outer membrane permeability of antibiotics against gram-negative bacteria. ACS Infect Dis 8:2339–2347. https://doi.org/10.1021/acsinfecdis.2c00406

Ye J, Chen X (2022) Current promising strategies against antibiotic-resistant bacterial infections. Antibiotics 12:67. https://doi.org/10.3390/antibiotics12010067

Yu L, Shang Z, Jin Q, Chan SY, Hong W, Li N, Li P (2023) Antibody-antimicrobial conjugates for combating antibiotic resistance. Adv Healthc Mater 12:2202207. https://doi.org/10.1002/adhm.202202207

Zadeh SM, Chen M-H, Wang Z-C et al (2022) β-Hydroxylation of α-amino-β-hydroxylbutanoyl-glycyluridine catalyzed by a nonheme hydroxylase ensures the maturation of caprazamycin. Commun Chem 5:87. https://doi.org/10.1038/s42004-022-00703-6

Zhang Q, Chen S, Liu X, Lin W, Zhu K (2021) Equisetin restores colistin sensitivity against multi-drug resistant gram-negative bacteria. Antibiotics 10:1263. https://doi.org/10.3390/antibiotics10101263

Zhang J, Cui X, Zhang M, Bai B, Yang Y, Fan S (2022) The antibacterial mechanism of perilla rosmarinic acid. Biotechnol Appl Biochem 69:1757–1764. https://doi.org/10.1002/bab.2248

Zhao X, Xu Y, Viel JH, Kuipers OP (2021) Semisynthetic macrocyclic lipo-lanthipeptides display antimicrobial activity against bacterial pathogens. ACS Synth Biol 10:1980–1991. https://doi.org/10.1021/acssynbio.1c00161

Zhou M, Qian Y, Xie J, Zhang W et al (2020) Poly(2-Oxazoline)-based functional peptide mimics: eradicating MRSA infections and persisters while alleviating antimicrobial resistance. Angew Chem Int Ed 59:6412–6419. https://doi.org/10.1002/anie.202000505

Download references

This research was sponsored by the National Natural Science Foundation of China (Grant No. 81873134), the Project of Philosophy and Social Science Research in Colleges and Universities in Jiangsu Province (Grant No. 2021SJA1939).

Author information

Authors and affiliations.

Jiangsu Vocational College of Medicine, Yancheng, China

Lei Chen & Hongyan Wu

School of Graduate Studies, Management and Science University, Shah Alam, Malaysia

Faculty of Health and Life Sciences, Management and Science University, Shah Alam, Malaysia

Suresh Kumar

You can also search for this author in PubMed   Google Scholar

Contributions

Conceptualization, SK; writing—original draft preparation, LC; writing—review and editing, SK; funding acquisition, HW. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Suresh Kumar .

Ethics declarations

Conflict of interest.

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the writing of the manuscript; or in the decision to publish the results.

Informed consent statement

Institutional review board statement, additional information.

Communicated by Yusuf Akhter.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Chen, L., Kumar, S. & Wu, H. A review of current antibiotic resistance and promising antibiotics with novel modes of action to combat antibiotic resistance. Arch Microbiol 205 , 356 (2023). https://doi.org/10.1007/s00203-023-03699-2

Download citation

Received : 25 August 2023

Revised : 25 September 2023

Accepted : 03 October 2023

Published : 20 October 2023

DOI : https://doi.org/10.1007/s00203-023-03699-2

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Antibiotic resistance
• Novel antibiotic candidates

Advertisement

• Find a journal
• Publish with us
• Track your research

Bacterial Antibiotic Resistance: The Most Critical Pathogens

Affiliations.

• 1 Department of Human Pathology, University of Messina, 98125 Messina, Italy.
• 2 IRCCS Centro Neurolesi "Bonino-Pulejo", 98100 Messina, Italy.
• PMID: 34684258
• PMCID: PMC8541462
• DOI: 10.3390/pathogens10101310

Antibiotics have made it possible to treat bacterial infections such as meningitis and bacteraemia that, prior to their introduction, were untreatable and consequently fatal. Unfortunately, in recent decades overuse and misuse of antibiotics as well as social and economic factors have accelerated the spread of antibiotic-resistant bacteria, making drug treatment ineffective. Currently, at least 700,000 people worldwide die each year due to antimicrobial resistance (AMR). Without new and better treatments, the World Health Organization (WHO) predicts that this number could rise to 10 million by 2050, highlighting a health concern not of secondary importance. In February 2017, in light of increasing antibiotic resistance, the WHO published a list of pathogens that includes the pathogens designated by the acronym ESKAPE ( Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species ) to which were given the highest "priority status" since they represent the great threat to humans. Understanding the resistance mechanisms of these bacteria is a key step in the development of new antimicrobial drugs to tackle drug-resistant bacteria. In this review, both the mode of action and the mechanisms of resistance of commonly used antimicrobials will be examined. It also discusses the current state of AMR in the most critical resistant bacteria as determined by the WHO's global priority pathogens list.

Keywords: ESBL; ESKAPE; carbapenem-resistant; multidrug-resistant.

Publication types

Better medical record-keeping needed to fight antibiotic overuse

A lack of detailed record-keeping in clinics and emergency departments may be getting in the way of reducing the inappropriate use of antibiotics, a pair of new studies by a pair of University of Michigan physicians and their colleagues suggests.

In one of the studies, about 10% of children and 35% of adults who got an antibiotic prescription during an office visit had no specific reason for the antibiotic in their record.

The rate of this type of prescribing is especially high in adults treated seen in emergency departments and in adults seen in clinics who have Medicaid coverage or no insurance, the studies show. But the issue also occurs in children.

Without information about what drove these inappropriate prescriptions, it will be even harder for clinics, hospitals and health insurers to take steps to ensure that antibiotics are prescribed only when they're really needed, the researchers say.

Overuse and misuse of antibiotics raise the risk that bacteria will evolve to resist the drugs and make them less useful for everyone. Inappropriately prescribed antibiotics may also end up doing more harm than good to patients.

"When clinicians don't record why they are prescribing antibiotics, it makes it difficult to estimate how many of those prescriptions are truly inappropriate, and to focus on reducing inappropriate prescribing," said Joseph Ladines-Lim, M.D., Ph.D., first author of both of the new studies and a combined internal medicine/pediatrics resident at Michigan Medicine, U-M's academic medical center.

"Our studies help contextualize the estimates of inappropriate prescribing that have been published previously," he added. "Those estimates don't distinguish between antibiotic prescriptions that are considered inappropriate due to inadequate coding and antibiotic prescriptions truly prescribed for a condition that they can't treat."

Ladines-Lim worked with U-M pediatrician and health care researcher Kao-Ping Chua, M.D., Ph.D., on the new studies. The one on outpatient prescribing by insurance status is in the Journal of General Internal Medicine and the one on trends in emergency department prescribing is in Antimicrobial Stewardship and Healthcare Epidemiology.

Building on previous research

Chua and colleagues recently published findings about trends in inappropriate antibiotic prescribing in outpatients under age 65, suggesting about 25% were inappropriate. But that number includes antibiotic prescriptions written for infectious conditions that antibiotics don't help, such as colds, and antibiotic prescriptions that aren't associated with any diagnoses that could be a plausible antibiotic indication.

The new studies add more nuance to that finding, by looking more closely at these two different types of inappropriate prescriptions.

Most antibiotic stewardship efforts to date have focused on reducing the use of the first type of inappropriate prescription -- those written for infectious but antibiotic-inappropriate conditions like colds. The new studies show such patients still account for 9% to 22% of all antibiotic prescriptions, depending on the setting and age group.

But since doctors and other prescribers aren't required to run a test for a bacterial infection or list a specific diagnosis in order to prescribe antibiotics, symptoms provide potential clues to why they might have written a prescription anyway.

So some of those 9% to 22% of all people receiving antibiotics may have also had a secondary bacterial infection that the clinician suspected based on symptoms.

However, it's impossible to know.

As for those with no infection-related diagnoses or symptoms in their records who got antibiotics, the researchers suggest that clinicians may not have bothered to add these diagnoses or symptoms to the patient record inadvertently -- or even deliberately, to try to avoid the scrutiny of antibiotic watchdogs.

But the researchers also speculate that the lower rate of diagnosis documentation in patients in the healthcare safety net may also have to do with the way healthcare organizations are reimbursed.

Often, clinics and hospitals receive a fixed amount from Medicaid to care for all their patients with that type of coverage. So they aren't incentivized to create records that are as detailed as for privately insured patients, whose care traditionally is reimbursed under a fee-for-service model.

"This could actually be a matter of health equity if people with low incomes or no insurance are being treated differently when it comes to antibiotics," says Ladines-Lim, who has also studied antibiotic use related to immigrant and asylum-seeker health and will soon begin a fellowship in infectious diseases.

He said that private and public insurers, and health systems, may need to incentivize accurate diagnosis coding for antibiotic prescriptions -- or at least make it easier for providers to document why they're giving them.

That might even include steps such as requiring providers to record the reason for antibiotic prescribing before prescriptions can be sent to pharmacies through electronic health record systems.

After all, Ladines-Lim said, physicians often have to list a diagnosis that justifies tests they order, such as CT scans or x-rays. With antibiotic resistance posing an international threat to patients who have antibiotic-susceptible conditions, similar steps to justify prescriptions of antibiotics might be advisable.

In addition to Ladines-Lim and Chua, the other authors of the two articles are Michael A. Fischer, M.D., M.S. of Boston Medical Center and Boston University, and Jeffrey A. Linder, M.D., M.P.H. of Northwestern University Feinberg School of Medicine.

The research was funded by a Resident Research Grant from the American Academy of Pediatrics, a Physician Investigator Award from Blue Cross Blue Shield Foundation of Michigan, and a Research Grant from the National Med-Peds Residents' Association.

• Today's Healthcare
• Infectious Diseases
• Diseases and Conditions
• Microbes and More
• Public Health
• STEM Education
• Disaster Plan
• Penicillin-like antibiotics
• Methylphenidate
• Antibiotic resistance
• Adult attention-deficit disorder
• Antiviral drug
• Antioxidant

Story Source:

Materials provided by Michigan Medicine - University of Michigan . Original written by Kara Gavin. Note: Content may be edited for style and length.

Journal References :

• Joseph Benigno Ladines-Lim, Michael A. Fischer, Jeffrey A. Linder, Kao-Ping Chua. Appropriateness of Antibiotic Prescribing in US Emergency Department Visits, 2016–2021 . Antimicrobial Stewardship & Healthcare Epidemiology , 2024; 4 (1) DOI: 10.1017/ash.2024.79
• Joseph B. Ladines-Lim, Michael A. Fischer, Jeffrey A. Linder, Kao-Ping Chua. Prevalence of Inappropriate Antibiotic Prescribing with or without a Plausible Antibiotic Indication among Safety-Net and Non-Safety Net Populations . Journal of General Internal Medicine , 2024; DOI: 10.1007/s11606-024-08757-z

Cite This Page :

Explore More

• High-Efficiency Photonic Integrated Circuit
• Life Expectancy May Increase by 5 Years by 2050
• Toward a Successful Vaccine for HIV
• Highly Efficient Thermoelectric Materials
• Toward Human Brain Gene Therapy
• Whale Families Learn Each Other's Vocal Style
• AI Can Answer Complex Physics Questions
• Otters Use Tools to Survive a Changing World
• Monogamy in Mice: Newly Evolved Type of Cell
• Sustainable Electronics, Doped With Air

Trending Topics

Strange & offbeat.

• Open access
• Published: 17 May 2024

Antibiotic susceptibility patterns and trends of the gram-negative bacteria isolated from the patients in the emergency departments in China: results of SMART 2016–2019

• Ying Fu 1 , 2 ,
• Feng Zhao 1 , 2 ,
• Jie Lin 1 , 2 ,
• Pengcheng Li 3 &
• Yunsong Yu 4 , 5 , 6  

BMC Infectious Diseases volume  24 , Article number:  501 ( 2024 ) Cite this article

14 Accesses

8 Altmetric

Metrics details

The study aims were to evaluate the species distribution and antimicrobial resistance profile of Gram-negative pathogens isolated from specimens of intra-abdominal infections (IAI), urinary tract infections (UTI), respiratory tract infections (RTI), and blood stream infections (BSI) in emergency departments (EDs) in China.

From 2016 to 2019, 656 isolates were collected from 18 hospitals across China. Minimum inhibitory concentrations were determined by CLSI broth microdilution and interpreted according to CLSI M100 (2021) guidelines. In addition, organ-specific weighted incidence antibiograms (OSWIAs) were constructed.

Escherichia coli ( E. coli ) and Klebsiella pneumoniae ( K. pneumoniae ) were the most common pathogens isolated from BSI, IAI and UTI, accounting for 80% of the Gram-negative clinical isolates, while Pseudomonas aeruginosa ( P. aeruginosa ) was mainly isolated from RTI. E. coli showed < 10% resistance rates to amikacin, colistin, ertapenem, imipenem, meropenem and piperacillin/tazobactam. K. pneumoniae exhibited low resistance rates only to colistin (6.4%) and amikacin (17.5%) with resistance rates of 25–29% to carbapenems. P. aeruginosa exhibited low resistance rates only to amikacin (13.4%), colistin (11.6%), and tobramycin (10.8%) with over 30% resistance to all traditional antipseudomonal antimicrobials including ceftazidime, cefepime, carbapenems and levofloxacin. OSWIAs were different at different infection sites. Among them, the susceptibility of RTI to conventional antibiotics was lower than for IAI, UTI or BSI.

Conclusions

Gram-negative bacteria collected from Chinese EDs exhibited high resistance to commonly used antibiotics. Susceptibilities were organ specific for different infection sites, knowledge which will be useful for guiding empirical therapies in the clinic.

Peer Review reports

Antimicrobials are frequently used in emergency departments (EDs) in China and a study noted that the proportion of emergency patients treated with antibiotics was as high as 39.31 to 43.45% from 2016 to 2019 [ 1 ]. Antibiotic stewardship in EDs should avoid administration of broad-spectrum antibiotics, shorten their use times, as well as minimizing their unnecessary use [ 2 ]. However, as patients presenting to EDs are often in an acute state, physicians have to make decisions in a very short time frame and they prescribe antibiotics empirically. For critically ill infected patients, guidelines recommend to start antibiotic treatment in the first hour of recognition [ 3 ], which means that it is frequently impossible to get microbiology results to guide the choice of antimicrobial therapy. In order to support the choice of empiric antibiotic treatments, consensus guidelines as well as local antibiotic drug susceptibility detection and various antimicrobial surveillance programs have been introduced in China [ 4 , 5 ].

One approach to individualized empiric antibiotic therapy is the Weighted-Incidence Syndromic Combination Antibiogram, which is comprised of information about the likelihood a treatment regimen will be effective for all relevant organisms for a given infection based on existing large datasets [ 6 , 7 , 8 ]. A similar approach is the organ-specific weighted incidence antibiogram (OSWIA), which estimates probable susceptibilities of organ specific isolates to specific antibiotics [ 9 ]. The Study for Monitoring Antimicrobial Resistance Trends (SMART) global surveillance program monitors in vitro susceptibilities of clinical Gram-negative bacilli to antimicrobial agents obtained from blood stream infections (BSI), intra-abdominal infections (IAI), urinary tract infections (UTI) and respiratory tract infections (RTI). The purpose of the present study was to determine the prevalence and susceptibilities of various bacteria to conventional antibiotics in patients attending Chinese EDs through a retrospective analysis of the SMART data collected from 2016 to 2019 and to determine differences of organ distributions between the infecting bacterial strains.

In this study, the patient informed consent was waived and authorized by the Ethics Committee of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine (Approval Number: 20210811-33).

All bacterial isolates were collected from discarded clinical specimens of hospitalized patients with BSI, IAI, UTI and RTI between 2016 and 2019 who were admitted to the EDs of 18 hospitals across China (Supplementary Table  1 ). The IAI specimen is derived from tissues or organs within the abdominal cavity, including the stomach, intestines, liver, spleen, pancreas, kidneys that have been infected by pathogens, resulting in infectious diseases [ 10 ]. RTI refers to an infection of the tissues in the respiratory system by pathogens such as viruses, bacteria, or fungi. RTI specimens from the respiratory tract included nasal and throat swabs, sputum samples, bronchoalveolar lavage fluid, respiratory secretions, and others [ 11 ]. Identification of isolates was initially made by each hospital laboratory and then the specimens were sent for laboratory re-identification using MALDI-TOF/MS (Bruker Daltonics, USA). Any duplicate isolates collected from the same patient were excluded from the data analysis.

Antimicrobial susceptibility testing

Testing was carried out in the Peking Union Medical College Hospital clinical microbiology laboratory using the Trek Diagnostic System (Thermo Fisher Scientific). Clinical isolates and reference strains were detected using the microbroth dilution method. Minimum inhibitory concentrations (MICs) were determined with reference to the antimicrobial breakpoint of the CLSI M100 (2021) [ 12 ]. The antibiotics tested were amikacin (AMK), cefepime (FEP), ceftazidime (CAZ), aztreonam (ATM), ceftriaxone (CRO), colistin (COL), ertapenem (ETP), levofloxacin (LVX), cefoxitin (FOX), imipenem (IPM), tobramycin (TOB), meropenem (MEM) and piperacillin–tazobactam (TZP).

Definition of antimicrobial-resistant strains

Carbapenem resistance of Escherichia coli ( E. coli ) and Klebsiella pneumoniae ( K. pneumoniae ) refers to resistance to any of IPM, MEM or ETP. Carbapenem-resistant Pseudomonas aeruginosa ( P. aeruginosa ) was defined as resistance to IPM or MEM.

Quinolone resistance to E. coli, K. pneumoniae and P. aeruginosa was defined as resistance to LVX.

Third generation cephalosporin resistance to E. coli and K. pneumoniae was defined as resistance to any CRO or CAZ, and the strains susceptible or intermediate to carbapenems (IPM, MEM or ETP). P. aeruginosa resistant to third-generation cephalosporin was defined as resistance to CAZ (CAZ-resistant PA) and the strains susceptible or intermediate to carbapenems (IPM, MEM).

OSWIA calculation

Data were retrospectively analyzed to establish the distribution of bacteria in various organs for BSI, IAI, UTI and RTI. OSWIA values were determined as previously described [ 9 ].

Patient characteristics and specimen source

Between January 01, 2016 and December 31, 2019, a total of 656 isolated were obtained from ED patients. The patient characteristics are detailed in Table  1 . The patients average age was 60.6 years (range: 1–101), comprising 388 males and 268 females. Most infections were hospital-acquired (HA) (58.1%), while 249 (38.0%) were community-acquired (CA) and for 26 data were not applicable. The isolates included 210 strains from IAI collected during surgery from the peritoneal fluid, appendix, abscesses, pancreas, gall bladder, liver and stomach. A total of 122 strains from BSI, 112 strains from UTI mainly from the urine, and 208 strains from RTI taken from bronchoalveolar lavage, endotracheal aspirate, thoracentesis or sputum were identified, as well as 4 strains from unconfirmed organs.

Distribution of Gram-negative bacteria obtained from BSI, IAI, UTI and RTI

Enterobacterales were the most common Gram-negative bacilli isolated from emergency patients with BSI, IAI and UTI (Fig.  1 ). E. coli accounted for 48.4% in BSI, 58.6% in IAI and 72.3% in UTI, while K. pneumoniae accounted for 24.6%, 21.4% and 11.6%, respectively and other Enterobacterales were much less common than E. coli and K. pneumoniae . The pathogen distribution in RTI was distinctly different from the other three infection types, with P. aeruginosa and K. pneumoniae being the most common species each accounting for about 40% of the Gram-negative pathogens. Since the composition ratio of Gram-negative bacteria was different at different infection sites (Fig.  1 , Supplementary Table  2 ) the varying patterns between infected organs should be considered when prescribing empirical treatments.

Distribution of Gram-negative bacilli in BSI, IAI, UTI and RTI. Abbreviations: BSI, blood steam infection; IAI, intra-abdominal infection; UTI, urinary tract infection

Distribution of Gram-negative bacteria from 2016 to 2019

The distribution of Gram-negative pathogens was stable between 2016 and 2019, with E. coli , K. pneumoniae and P. aeruginosa being the top 3 species, accounting for more than 80% of the clinical isolates (Fig. 2 , Supplementary Table 3 ).

Composition ratio of Gram-negative bacteria in EDs from 2016 to 2019.  Abbreviation: ED, emergency department.

Distribution of Gram-negative bacteria in different age groups of patients

Among the strains collected, regardless of the organ of origin, the predominant species were P. aeruginosa, E. coli and K. pneumoniae . However, the composition ratio of the main bacterial groups were different in infection sites within age groups (Fig.  3 a-d) and were generally different especially in the age group ≤ 39 years (Fig.  3 e, Supplementary Table  4 ).

Comparison of the composition ratio of microbiota in different infected organs and age groups.  Abbreviations: BSI, blood steam infection; IAI, intra-abdominal infection; RTI, respiratory tract infection; UTI, urinary tract infection.

Monitoring of drug susceptibility

Drug resistance rate monitoring of major gram-negative bacteria from 2016 to 2019.

E. coli exhibited < 10% resistance to AMK, COL, ETP, IPM, MEM and TZP, with the exception in 2016 to TZP, but generally TZP resistance rates were reduced between 2016 and 2019. Otherwise, resistance rates were more than 30%, with the exception of FOX (16.2%). K. pneumoniae exhibited < 20% resistance only to AMK and 6.4% to COL between 2016 and 2019. P. aeruginosa only exhibited low resistant rates of 13.4% to AMK, 11.6% to COL and 10.8% to TOB from 2016 to 2019 (Table  2 ).

Detection rate and drug susceptibility of specific antibiotic-resistant bacteria from 2016 to 2019

Isolation of carbapenem-resistant, quinolone-resistant or third-generation cephalosporin-resistant e. coli, k. pneumoniae and p. aeruginosa.

In isolates, the carbapenem-resistant E. coli and P. aeruginosa showed an overall downward trend. However, the rate of detection of carbapenem-resistant E. coli was relatively low, being only 1.3% in 2019, while for carbapenem-resistant P. aeruginosa  in 2019 it was 30.0% and for carbapenem-resistant K. pneumoniae strains in 2019, 34.1%, the rate being higher than in 2018 (18.5%). The rate of detection of quinolone-resistant E. coli  or  K. pneumoniae showed a decreasing trend in the four years studied, being 55.7% in 2019 for the detection of quinolone-resistant E. coli  and 36.4% for K. pneumoniae . The detection rate of quinolone-resistant P. aeruginosa was 26.7% in 2019 and lower than in 2018 (42.9%). The detection rates of third-generation cephalosporin-resistant E. coli and K. pneumoniae as well as P. aeruginosa showed an irregular trend from 2016 to 2019, being between 44.3%–63.2% and 9.1%–24.1% as well as 2.9%–15.4%, respectively throughout the years. Compared to E. coli, there were only few numbers of third-generation cephalosporin-resistant K. pneumoniae and P. aeruginosa isolates found between 2016 and 2019 (Fig. 4 , Supplementary Table 5 ).

Isolation (detection) rate of carbapenem-resistant, quinolone-resistant, third-generation cephalosporin-resistant E. coli , K. pneumoniae  and P. aeruginosa from 2016 to 2019

Specific drug resistance rates (%) of strains to antibiotics from 2016 to 2019

For E. coli , the resistance rate of carbapenem-resistant E. coli to AMK was 33.3%, and to the other antibiotics tested were > 60%, apart from COL (25.0%). Quinolone-resistant E. coli exhibited the lowest resistance rates to AMK (4.3%), ETP (5.6%), IPM (5.0%) and MEM (5.6%). The resistance rates of third-generation cephalosporin-resistant E. coli was 2.0% to AMK and 0% to ETP, IPM and MEM.

Carbapenem-resistant K. pneumoniae were 57.1% resistant to AMK and quinolone-resistant K. pneumoniae were 42.0% resistant to AMK, with low resistance rates only found to COL (8.2% and 10.1%), respectively. Third-generation cephalosporin-resistant K. pneumoniae was 6.7% resistant to AMK and 0% to ETP, IPM and MEM.

For carbapenem-resistant P. aeruginosa , the drug resistance to AMK was 30.4%, for TOB 28.0% and for COL (10.9%). For quinolone-resistant  P. aeruginosa, only resistance rates to AMK (24.4%) and TOB (26.1%) as well as COL (9.8%) remained low. Third-generation cephalosporins resistant  P. aeruginosa, showed low resistance rates of 0% to AMK, IPM, MEM and TOB (Table 3 ).

Antimicrobial susceptibility monitoring during empiric treatment of different infection sites and organs

In the weighted susceptibility assessment of different infection sites, it was found that the susceptibility of the same antibacterial drug at different organs and infection sites was different. For example, AMK, TOB, ETP, IPM and MEM were the antibiotics with > 90% susceptibility for BSI, but only AMK and MEM were > 90% effective antibiotics against IAI. High-susceptibility to antibiotics in UTI included AMK, TOB and MEM (all > 90%), and except for AMK, COL and TOB, the susceptibility to other antibiotics at the site of RTI infections was < 80% (Fig. 5 , Supplementary Table 6 ).

Organ distribution related susceptibilities. a Differences in susceptibility of antibiotics at different infection sites. b Differences in weighted drug susceptibilities of antibiotics at different organs and infection sites. Note: *only sites from which more than 10 pathogenic bacteria were collected have been included; #, intermediate rate was shown for COL; -, no detection. Abbreviations: AMK, amikacin; ATM, aztreonam; BSI, blood steam infections; CAZ, ceftazidime; CRO, ceftriaxone; ETP, ertapenem; FEP, cefepime; FOX, cefoxitin; IAI, intra-abdominal infections; IPM, imipenem; LVX, levofloxacin; MEM, meropenem; RTI, respiratory tract infections; TOB, tobramycin; TZP, piperacillin/tazobactam; UTI, urinary tract infections

This study analyzed Chinese data from the global SMART surveilance program and found that the most frequently isolated Gram-negative bacteria were Enterobacterales , a finding similar to previous results from SMART studies and the China Antimicrobial Surveillance Network (CHINET) [ 13 , 14 ]. Enterobacterales are of particular concern given their ability to develop and spread resistance to penicillins, cephalosporins, carbapenems and quinolones [ 12 , 15 , 16 ]. As these are the most commonly used antibiotics in hospitals, such resistance would leave physicians with very limited treatment options. The vast majority of the pathogens were E. coli , K. pneumoniae and P. aeruginosa  (86.4%), with resistance rates for cephalosporins in the range of 31.0%–57.0% and for ATM 44.0%–45.5%, indicating a high rate of ESBL-producing strains [ 17 ], which underlines the global health problem of cephalosporin resistance [ 18 ]. Previous SMART surveilence results found ESBL rates of 46.3%–49.1% for E. coli and 25.6%–26.8% for K. pneumoniae [ 13 ]. In the 2021 CHINET surveillance, resistance to third-generation cephalosporins was detected in 55.6% of E. coli and 43.8% of K. pneumoniae , also indicating the high ESBL prevalence in China [ 14 ]. The resistance rates for the fluoroquinolone LVX (36.6%–56.7%) were in a similar range to cephalosporins in this study, which might reflect the overuse of fluoroquinolones, especially since the development of cephalosporin-resistance [ 19 , 20 ]. They were similar to the rates reported by the 2021 CHINET surveillance of LVX resistance detected as 53.6% for E. coli and 28.3% for K. pneumoniae isolates [ 14 ]. One approach to overcome cephalosporin resistance is the use of combination of a β-lactam and a β-lactamase inhibitor [ 21 ], such as tazobactam, which led to essentially reduced resistance rates of about 10% for otherwise cephalosporin-resistant E. coli and K. pneumoniae in the present study. Of concern is the rising resistance rate of K. pneumoniae to carbapenems , which reached25%–29% in the present study and was similar to the rate of about 25% found in the 2021 CHINET surveillance study [ 14 ].

Resistance rates for COL were generally low, but susceptibility breakpoints have been abolished in recent CLSI guidelines. Treatments with COL should be applied with maximum renally adjusted doses, since the previous MIC of 2 μg/mL could not be achieved in 50% of patients with normal renal functions and acute kidney injury occurs frequently with conventional doses. Recommendations include strongly preferred alternative drugs for active or combination treatments [ 22 , 23 ]. Also, TOB is not commonly used in China, which might explain the low resistance rates found in the present study.

P. aeruginosa was the third most common pathogen detected and the most common Gram-negative pathogen found in RTI. It exhibited > 30% resistance to traditional antipesudomoas antibiotics, including CAZ, FEP, TZP, IPM, MEM and LVX. These results are similar to those reported in a recent SMART study that investigated P. seudomonas resistance to antibiotics in China [ 24 ].

This present survey included only isolates collected in EDs, since patients admitted to EDs are frequently candidates for urgent empiric antibiotic treatment, which should be administered according to the site of infection and the clinical severity of symptoms [ 25 ]. The characteristics of infected patients and physicians' routine treatments in the ED differed compared to other departments. This is because the infected site may initially not be clearly defined, patients cannot be observed for a long period of time, and etiological evidence is rarely available; doctors and nurses in EDs also have a very heavy workload. It is therefore convenient to use drugs which only need administration once a day to ED patients, including ETP once a day, AMK intramuscular injection, as well as LVX once a day, which can be sequenced simultaneously.

In order to offer guidelines for chosing an empiric treatment, organ specific therapy based on pathogen distribution differences and their antibiotic resistance variations have been developed [ 6 , 8 ]. Of these, OSIWA was first applied for HA and CA infections of different intra-abdominal organs [ 9 ]. In the present study, we expanded the evaluation of OSIWA for the empirical treatment of IAI also to UTI, BSI and RTI. When considering the distribution of pathogens at a single infection site – for example E. coli  caused more than 50% of all IAI and more than 60% of all UTI – whereas for RTI infections E. coli  was the pathogen in < 15% of all cases (Fig. 3 ). The OSIWA shown in Fig 5  indicate the probabilities of successful empiric drug treatment for single infections sites. For RTI and IAI the choice of empirical antibiotics with expected efficacy was limited, but for UTI and BSI more antibiotics are available.

Limitations of the present survey were the relatively low sample numbers since only isolates from EDs have been included, which have had an influence on the resistance patterns reported and combination treatments with β-lactams, aminoglycoside and fluoroquinolone were not considered. In addition, since in the SMART data collection detailed data regarding resistance mechanisms are not included, susceptibility test results only can infer the mechanism of ESBL production in cephalosporin but not in carbapenem resistance.

The pathogens isolated from BSI, IAI, UTI and RTI between 2016 and 2019 in Chinese EDs were mainly E. coli, K. pneumoniae and P. aeruginosa ,but therewere considerable resistance pattern differences as well as organ distributions between the bacterial strains. OSIWA determinations led to organ specific antibiotic drug effectiveness patterns, which should help to guide the choice of suitable empirical antibiotic treatments, especially for urgent infected cases in EDs.

Availability of data and materials

The SMART database is not public and is only accessible to SMART investigators, but the data that support the findings of this study are directly available from MSD China or from the corresponding author Yunsong Yu upon reasonable request and with permission of MSD China. 

Abbreviations

blood stream infections

community acquired

ceftazidime

China Antimicrobial Surveillance Network

ceftriaxone

emergency departments

hospital acquired

intra-abdominal infections

levofloxacin

minimum inhibitory concentrations

organ-specific weighted incidence antibiograms

respiratory tract infections.

Study for Monitoring Antimicrobial Resistance Trends

piperacillin–tazobactam

urinary tract infections

Zhu Y, Qiao Y, Dai R, Hu X, Li X. Trends and patterns of antibiotics use in China’s Urban tertiary hospitals, 2016-19. Front Pharmacol. 2021;12:757309.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Luyt C-E, Bréchot N, Trouillet J-L, Chastre J. Antibiotic stewardship in the intensive care unit. Crit Care. 2014;18(5):480.

Article   PubMed   PubMed Central   Google Scholar  

Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med. 2021;49(11):e1063-1143.

Article   PubMed   Google Scholar  

Hay SI, Rao PC, Dolecek C, Day NPJ, Stergachis A, Lopez AD, et al. Measuring and mapping the global burden of antimicrobial resistance. BMC Med. 2018;16(1):78.

Schnall J, Rajkhowa A, Ikuta K, Rao P, Moore CE. Surveillance and monitoring of antimicrobial resistance: limitations and lessons from the GRAM project. BMC Med. 2019;17(1):176.

Randhawa V, Sarwar S, Walker S, Elligsen M, Palmay L, Daneman N. Weighted-incidence syndromic combination antibiograms to guide empiric treatment of critical care infections: a retrospective cohort study. Crit Care. 2014;18(3):R112.

Cook A, Sharland M, Yau Y, Group* P, Bielicki J. Improving empiric antibiotic prescribing in pediatric bloodstream infections: a potential application of weighted-incidence syndromic combination antibiograms (WISCA). Expert Rev Anti Infect Ther. 2022;20(3):445–56.

Article   CAS   PubMed   Google Scholar  

Hebert C, Ridgway J, Vekhter B, Brown EC, Weber SG, Robicsek A. Demonstration of the weighted-incidence syndromic combination antibiogram: an empiric prescribing decision aid. Infect Control Hosp Epidemiol. 2012;33(4):381–8.

Liu L, Ni Y. Antimicrobial susceptibilities of specific syndromes created with organ-specific weighted incidence antibiograms (OSWIA) in patients with intra-abdominal infections. BMC Infect Dis. 2018;18(1):584.

Chinese Society of Surgical Infection and Intensive Care, Chinese Society of Surgery, Chinese Medical Association. Chinese College of Gastrointestinal Fistula Surgeons, Chinese College of Surgeons, Chinese Medical Doctor Association. Chinese guideline for the diagnosis and management of intra-abdominal infection (2019 edition). Chin J Practical Surg. 2020;40(1):1–16.

Google Scholar  

Chinese Medical Association. Clinical Guidelines: Respiratory diseases. Beijing: People’s Medical Publishing House; 2009. p. 174.

Nordmann P, Poirel L. Emergence of plasmid-mediated resistance to quinolones in enterobacteriaceae. J Antimicrob Chemother. 2005;56(3):463–9.

Zhang H, Johnson A, Zhang G, Yang Y, Zhang J, Li D, et al. Susceptibilities of Gram-negative bacilli from hospital- and community-acquired intra-abdominal and urinary tract infections: a 2016–2017 update of the Chinese SMART study. Infect Drug Resist. 2019;12:905–14.

Fupin HU, Yan GUO, Demei ZHU, Fu W, Xiaofei J, Yingchun XU, et al. CHINET surveillance of antimicrobial resistance among the bacterial isolates in 2021. Chin J Infect Chemother. 2022;22(5):521–30.

Ma J, Song X, Li M, Yu Z, Cheng W, Yu Z, et al. Global spread of carbapenem-resistant Enterobacteriaceae: Epidemiological features, resistance mechanisms, detection and therapy. Microbiol Res. 2023;266:127249.

De Angelis G, Del Giacomo P, Posteraro B, Sanguinetti M, Tumbarello M. Molecular mechanisms, epidemiology, and clinical importance of beta-lactam resistance in enterobacteriaceae. Int J Mol Sci. 2020;21(14):5090.

Rawat D, Nair D. Extended-spectrum β-lactamases in gram negative bacteria. J Glob Infect Dis. 2010;2(3):263–74.

Pana ZD, Zaoutis T. Treatment of extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBLs) infections: what have we learned until now? F1000Res.2018;7:F1000 Faculty Rev-1347.

Ezelarab HAA, Abbas SH, Hassan HA, Abuo-Rahma GEA. Recent updates of fluoroquinolones as antibacterial agents. Arch Pharm (Weinheim). 2018;351(9):e1800141.

Hou J, Long X, Wang X, Li L, Mao D, Luo Y, et al. Global trend of antimicrobial resistance in common bacterial pathogens in response to antibiotic consumption. J Hazard Mater. 2023;442:130042.

Yahav D, Giske CG, Grāmatniece A, Abodakpi H, Tam VH, Leibovici L. New β-Lactam-β-Lactamase Inhibitor Combinations. Clin Microbiol Rev. 2020;34(1);e00115.

Satlin MJ, Lewis JS, Weinstein MP, Patel J, Humphries RM, Kahlmeter G, et al. Clinical and laboratory standards institute and European committee on antimicrobial susceptibility testing position statements on polymyxin b and colistin clinical breakpoints. Clin Infect Dis. 2020;71(9):e523-529.

CAS   PubMed   Google Scholar  

Tsuji BT, Pogue JM, Zavascki AP, Paul M, Daikos GL, Forrest A, et al. International consensus guidelines for the optimal use of the polymyxins: endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti-infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). Pharmacotherapy. 2019;39(1):10–39.

Croche Santander B, Campos Alonso E, Sanchez Carrion A, Marcos Fuentes L, Diaz Flores I, Vargas JC, et al. [Appropriateness of antibiotic prescribing in paediatric patients in a hospital emergency department]. Pediatr (Engl Ed). 2018;88(5):259–65.

Kollef MH, Shorr AF, Bassetti M, Timsit J-F, Micek ST, Michelson AP, et al. Timing of antibiotic therapy in the ICU. Crit Care. 2021;25(1):360.

Download references

Acknowledgements

The authors thank Shanghai BIOMED Science Technology Co., Ltd (Shanghai, China) for providing editorial assistance and MSD China for their financial support.

This study was sponsored by funding from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA. The funding body was involved in the study design, analysis and interpretation of data, as well as the decision to submit the article for publication.

Author information

Authors and affiliations.

Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 310016, Hangzhou, Zhejiang Province, China

Ying Fu, Feng Zhao & Jie Lin

Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, 310016, Hangzhou, Zhejiang Province, China

MRL Global Medical Affairs, MSD China, 200233, Shanghai, China

Pengcheng Li

Department of Infectious Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 310016, Hangzhou, Zhejiang Province, China

Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, 310012, Hangzhou, Zhejiang Province, China

Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 310016, Hangzhou, Zhejiang Province, China

You can also search for this author in PubMed   Google Scholar

Contributions

All authors made substantial contributions to the conception and design of the study, acquisition of data, or analysis and interpretation of data, took part in drafting the manuscript or critically revising it for important intellectual content, agreed to submit it to the current journal, gave final approval of the version to be published and agreed to be accountable for all aspects of the work.

Corresponding author

Correspondence to Yunsong Yu .

Ethics declarations

Ethical approval and consent to participate, consent for publication.

Not applicable.

Competing interests

Pengcheng Li is an employee of MSD China. All other authors declare no competing interests.

Additional information

Publisher’s note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Supplementary material 1., rights and permissions.

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article.

Fu, Y., Zhao, F., Lin, J. et al. Antibiotic susceptibility patterns and trends of the gram-negative bacteria isolated from the patients in the emergency departments in China: results of SMART 2016–2019. BMC Infect Dis 24 , 501 (2024). https://doi.org/10.1186/s12879-024-09294-0

Download citation

Received : 14 December 2023

Accepted : 05 April 2024

Published : 17 May 2024

DOI : https://doi.org/10.1186/s12879-024-09294-0

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Antibiogram
• Cephalosporin
• Antibiotic-Resistance

BMC Infectious Diseases

ISSN: 1471-2334

• Submission enquiries: [email protected]
• General enquiries: [email protected]

share this!

May 13, 2024

This article has been reviewed according to Science X's editorial process and policies . Editors have highlighted the following attributes while ensuring the content's credibility:

fact-checked

peer-reviewed publication

trusted source

Researchers find new approach for antibiotic development

by Arne Claussen, Heinrich-Heine University Duesseldorf

The opportunistic bacterial pathogen Pseudomonas aeruginosa is dangerous due to its resistance to multiple antibiotics. A research team from Heinrich Heine University Düsseldorf (HHU) and Jülich Research Center (Forschungszentrum Jülich—FZJ) has now found a mechanism that makes it possible to weaken the virulence of the pathogen.

Based on this knowledge, a new approach for antibiotics can be developed, as the authors explain in JACS Au . The editors of the journal have dedicated a cover story to this discovery.

The bacterium Pseudomonas aeruginosa often causes a so-called "nosocomial infection" in humans. It is therefore one of the dangerous hospital bacteria that is resistant to several antibiotics. Immunocompromised patients are particularly affected. The World Health Organization (WHO) has placed P. aeruginosa on the list of "priority pathogens" on which research efforts should focus to find new treatment options.

The bacterium has a broad spectrum of disease-causing virulence factors. These include the "type A phospholipases" (PLA1): Enzymes that can damage the membrane of the host cell and also disrupt various signaling networks in the infected cells. Preliminary work has shown that the enzyme PlaF from P. aeruginosa is a PLA1 that also alters the membrane profile and thus contributes to the virulence of the bacterium.

The research groups of Professor Dr. Holger Gohlke (HHU Institute of Pharmaceutical and Medicinal Chemistry and IBG-4: Bioinformatics at FZJ) and Professor Dr. Karl-Erich Jaeger (HHU Institute of Molecular Enzyme Technology at FZJ) have now identified molecular mechanisms in which medium-chain free fatty acids regulate the activity of PlaF.

The researchers carried out molecular simulations as well as laboratory studies and in vivo assays. All of these research approaches showed an indirect effect of the fatty acids on the location of PlaF in the bacterial membrane as well as a direct effect by blocking the active center of the enzyme. In both ways, the activity of PlaF is reduced.

On the one hand, the results provide evidence that the interplay of mechanisms is a regulatory factor for PlaF function. Professor Gohlke, "We were only able to unravel these complex relationships through the interaction of computer-aided and experimental techniques within the framework of the projects funded by the CRC 1208."

On the other hand, the results contribute to understanding the regulatory role of fatty acids. It may be possible to transfer the results to other membrane proteins that have a similar structure to PlaF.

Finally, they also open up new perspectives on how PlaF can be inhibited. Professor Jaeger, "This is a promising approach for developing new antibiotics against P. aeruginosa. These are urgently needed to combat the dangerous pathogens in hospitals."

Journal information: JACS Au

Provided by Heinrich-Heine University Duesseldorf

Explore further

Feedback to editors

Blue Origin flies thrill seekers to space after two year hiatus

4 hours ago

Composition of gut microbiota could influence decision-making

May 18, 2024

Researchers realize multiphoton electron emission with non-classical light

Saturday Citations: Mediterranean diet racks up more points; persistent quantum coherence; vegan dogs

Physicists propose path to faster, more flexible robots

Scientists develop new geochemical 'fingerprint' to trace contaminants in fertilizer

May 17, 2024

Study reveals how a sugar-sensing protein acts as a 'machine' to switch plant growth—and oil production—on and off

Researchers develop world's smallest quantum light detector on a silicon chip

How heat waves are affecting Arctic phytoplankton

Horse remains show Pagan-Christian trade networks supplied horses from overseas for the last horse sacrifices in Europe

Relevant physicsforums posts, most dangerous chemicals.

3 hours ago

My 'why' questions -- Wanting to learn Chemistry to figure out my why questions

11 hours ago

Potassium Iodide as a catalyst for Hydrogen Peroxide

May 15, 2024

Very confused about Naunyn definition of acid and base

Ideas for a project in computational chemistry, why don't hydrogen ions have osmotic activity in living organisms.

May 6, 2024

More from Chemistry

Related Stories

Global collaboration discovers drug target to combat chronic lung infection

Apr 10, 2024

Scientists discover novel antibodies that target resistant bacteria

Nov 2, 2023

New starting point discovered in the fight against P. aeruginosa

Mar 14, 2024

Study reveals fatty acids hold clue to creating memories

Feb 6, 2024

Using phages to eradicate Pseudomonas aeruginosa infections

Feb 21, 2024

New approach can help counter antibiotic resistance

Mar 30, 2023

Recommended for you

Chemists develop new method for making gamma chiral centers on simple carboxylic acids

Breaking bonds to form bonds: New chemical reaction with potential applications in medicinal chemistry

May 16, 2024

A second chance for a new antibiotic agent

Research team achieves rapid and reliable room-temperature phosphorescence chiral recognition

Temperature, time and blueberry wine: Researchers examine fermentation's effects on health-promoting compounds

Bio-based resins could offer recyclable future for 3D printing

Let us know if there is a problem with our content.

Use this form if you have come across a typo, inaccuracy or would like to send an edit request for the content on this page. For general inquiries, please use our contact form . For general feedback, use the public comments section below (please adhere to guidelines ).

Please select the most appropriate category to facilitate processing of your request

Thank you for taking time to provide your feedback to the editors.

Your feedback is important to us. However, we do not guarantee individual replies due to the high volume of messages.

E-mail the story

Your email address is used only to let the recipient know who sent the email. Neither your address nor the recipient's address will be used for any other purpose. The information you enter will appear in your e-mail message and is not retained by Phys.org in any form.

Newsletter sign up

Get weekly and/or daily updates delivered to your inbox. You can unsubscribe at any time and we'll never share your details to third parties.

More information Privacy policy

Donate and enjoy an ad-free experience

We keep our content available to everyone. Consider supporting Science X's mission by getting a premium account.

E-mail newsletter

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• Infect Drug Resist

Evidence of Antibiotic Resistance from Population-Based Studies: A Narrative Review

Elisa giacomini.

1 CliCon S.r.l. Health, Economics & Outcomes Research, Ravenna, Italy

Valentina Perrone

Davide alessandrini, daniela paoli, carmela nappi, luca degli esposti.

The 20th century witnessed the dawn of the antibiotic revolution and is now facing the rising phenomenon of antibiotic resistance. In this narrative review, we aim to describe antibiotic resistance in clinical practice settings through population-based studies from different countries reporting the role of misuse of antibiotics in the development of resistance and the clinical and economic burden associated. The misuse of antibiotics was documented in the wide population as well as in hospitals and care facilities. It was mainly reported as over-use and inappropriate prescribing. Improper dosage regimens and longer treatment duration were regarded as pivotal factors related to antibiotic resistance; the emerging strategy of “antibiotic-de-escalation” could be the key to overcome these issues. The investigation of the self-medication attitude revealed widespread antibiotic use without following medical instructions or medical consultation. Moreover, several studies established the association of antibiotic resistance with increased risk of longer hospitalizations and mortality, highlighting the heavy clinical and economic burden of this phenomenon. In this narrative review, the widespread inappropriate use of antibiotics emerged as one of the main causes of antibiotic resistance, which negative outcomes call for the development of antibiotic stewardship programs and global surveillance networks.

Introduction

Overview of antibiotic resistance.

The discovery of penicillin by Alexander Fleming in 1928 marked the beginning of the antibiotics era, it looked like the struggle of mankind against infections was finally over thanks to these powerful weapons. Use of antibiotics and the introduction of vaccination have increased life expectancy, decreased childhood mortality and allowed invasive surgery and chemotherapy treatments. 1 However, we are still far away to win that battle, as we have to face the threat of antibiotic resistance (ABR).

ABR is defined as the ability of microorganisms to survive to the exposure of antibiotics that normally would be able to kill them or to stop their growth. 2 The rising of a phenotype resistant to antimicrobial agents depends on several factors such as degree of resistance expression of the microorganism or its capability to tolerate resistance mechanism, to cite a few. 3 Bacteria may have intrinsic resistance or acquire resistance from either mutations in cell genes (chromosomal mutation) leading to cross-resistance, or gene transfer from one microorganism to another mediated by plasmids, transposons, integrons and bacteriophages. When resistance determinants are on plasmids, resistant microorganisms will spread quickly. 3 Several biochemical types of resistance mechanisms can be used by the bacteria to protect themselves from various agents, the most important mechanisms being enzymatic degradation, target alteration, decreased uptake and overexpression of efflux pump proteins. 4

Even though this phenomenon is a natural process observed in clinical practice since the first-generation antibiotics, 5 ABR is nowadays regarded as a global public health concern due to the rising rate of resistance development and spreading and the lack of new drugs able to contain it. 6 The development of non-susceptibility to the novel antibiotics is deemed as inevitable and potentially leads to a shortened period of clinical usefulness of these drugs. 7 Based on their resistance levels and clinical significance, the World Health Organization declared the so-called “ESKAPE” pathogens (E: Enterococcus faecium , S: Staphylococcus aureus or Stenotrophomonas maltophilia , K: Klebsiella pneumoniae or C: Clostridioides difficile , A: Acinetobacter baumannii , P: Pseudomonas aeruginosa , E: Enterobacteriaceae) as priority pathogens for pharmaceutical companies. 7

The dimension of ABR is also mirrored in the increasing number of publications focused on this topic over the past seventy years ( Figure 1 ).

Timeline of publications indexed on PubMed related to ABR.

The Sixty-eight World Health Assembly responded to the rising alarm of ABR by launching in 2015 a global action plan with the aim to optimize the use of antibiotic agents, to make these drugs accessible to all who need them and to increase knowledge and awareness on ABR, thus ensuring the continuity of successful treatment and prevention of infectious diseases. 8

ABR affects all areas of health, from human sector to animal and environment, thus involving society as a whole. 8 Antibiotics are indeed prescribed not only for the treatment of infectious diseases among humans and animals, but they are widely used in the food industry, to increase meat production. 9 , 10 A high proportion of administered antibiotics is discharged into water and soil through wastewater treatment plants, animal manure, sewage sludge, and biosolids frequently used to irrigate and fertilize agricultural lands. 10 The release of antimicrobial agents into the aquatic environment and soil creates the conditions for the development of antibiotic resistant bacteria and the environmental occurrence of antibiotic resistant genes. 9 Some of the main causes of ABR are listed in Figure 2 .

Main factors leading to antibiotic resistance.

The present review focuses specifically on ABR threat in humans, to highlight the attitude towards ABR in clinical practice settings all over the world.

ABR in Clinical Practice

The emergence of ABR was typically considered as a problem predominantly concerning hospitals and care facilities, however in the recent years resistant bacteria have been seen to spread in the wider community as well, leading to an increase in both the population at risk and the number of resistant infections. 11 , 12 The misuse and abuse of antibiotics in clinical practice are among the main perpetrators for ABR and are now likely to undermine the incredible progress brought by antibiotics in modern medicine, including management of life-threatening infectious diseases or conditions such as cancer and advances made in surgical procedures, from caesarean sections to organ transplants. 6

Infections are included among the major causes of death in the developing world and one of the responsible actors is the reappearance of once-controlled diseases due to ABR. 13 Data on the epidemiology of infections caused by resistant bacteria are however scarce because of poor reporting and surveillance; in addition, the choice of the appropriate study design or statistical methods to calculate the incidence, risk of death or other clinical outcomes associated to infections with ABR bacteria is still open to debate. 14–16 Cassini and co-workers recently provided an estimation of the burden of such infections based on data collected from the European Antimicrobial Resistance Surveillance Network (EARS-Net) in 2015. 14 Their findings showed that in the European Union and European Economic Area (EEA) countries, the number of cases of all types of infections (bloodstream, urinary tract, respiratory tract, surgical site and other infections) due to the selected ABR bacteria of public health importance was 671,689 (incidence of 131 infections per 100,000 population), 63.5% of which associated with health-care facilities (hospitals and other health-care settings). Deaths attributable to these infections were estimated to be 33,110 (incidence of 6.44 deaths per 100,000 population), with approximately 11,000 reported only in Italy. Moreover, the authors for the first time reported the burden of infections for ABR expressed in disability-adjusted life-years (DALYs), that were found to be 874,541, with overall DALY of 170 per 100,000 population, similar to the combined burden of HIV, influenza, and tuberculosis in 2015. The final “Review of antimicrobial resistance” chaired by O’Neill 6 warned that, according to their estimation, ABR could cause approximately 10 million deaths yearly by 2050 unless global action is taken.

The picture described above is also exacerbated by the economic burden of ABR: a recent systematic review reported that health-care system costs were up to $1 billion per year and estimated over $3 trillion in Gross Domestic Product (GDP) loss. 17

The aim of this review is to describe from a clinical practice standpoint the inappropriate use of antibiotics in terms of over-use, self-prescription, improper dosage regimens and treatment duration and to summarise the avoidable clinical outcomes and economic burden evaluated in observational studies ( Figure 3 ).

Concept scheme: causes and consequences of antibiotic resistance in clinical practice.

Development of ABR in Clinical Practice: The Role of Inappropriate Use of Antibiotics

The inappropriate use of antibiotics is regarded as one of the main contributors to ABR onset. The misuse refers to high consumption of antibiotics, often unnecessarily, and it comprises over-use, inappropriate prescribing, self-medication, negligent use or incorrect dosage or treatment duration. 18–20 Antibiotics misuse can be a consequence of patients’ attitude, 21 as evidenced by the high prevalence of use of antibiotics without prescription or by patients arbitrarily not following doctors’ instructions nor the indication on the duration and dosage of treatments reported in the summary of product characteristics. 22–24 Community pharmacists play a role too, in ensuring a cautious use of antibiotics. 25

On the other hand, from a physicians’ point of view, efforts should be made to optimize prescription patterns to avoid inappropriate antibiotic use – especially in primary health-care – in terms of over-prescription. 26 , 27 In this regard, therapeutic inertia 28 may play a role in using antibiotics for prolonged times when there are concerns about the outcome, uncertainty of diagnosis or in case of appearance of nonspecific symptoms. 29 , 30

The adoption of guidelines/recommendations to guide the empirical choice of antibiotic therapy is pivotal. To this aim, Elias et al 31 reviewed international guidelines of five frequent infectious syndromes (community-acquired pneumonia, urinary tract infections, acute otitis media, rhinosinusitis and pharyngitis) to evaluate the role of resistance patterns in the clinical decision-making. Disappointingly, the authors found in around two-thirds of the guidelines empiric recommendations not supported by data on resistance patterns, and very few guidelines reporting country-specific resistance patterns. Similar conclusions could be drawn for other medical areas as well: for instance, in the ophthalmology field, the standard of care is regarded from Miller 32 as “to treat first and culture later”, and Grosso et al 33 solicit that the use of antibiotics in ophthalmic surgery should be driven also by local microorganism surveillance. Moreover, Steels and van Staa 34 observed that there is a need for bringing more clinically relevant evidence into guidelines to improve their uptake in clinical practice.

Several real-world studies performed in different countries highlighted the issue of antibiotic misuse and are reported in the following.

Considering studies based on the wide community, Smieszek et al 35 performed a retrospective analysis based on the Health Improvement Network (THIN) database from 2013 to 2015 with the aim to quantify the inappropriate prescribing in primary care in England. Specifically, the authors focused on the over-prescription phenomenon, defined as “any antibiotic prescribing that is likely to have marginal or zero patient benefit and be outweighed by the potential risks of prescribing”. To discriminate between appropriate and inappropriate prescribing, the authors took into account the treatment guidelines, the expert opinion of “ideal” prescribing proportions for defined conditions, and the variation in prescribing to identify over-prescription. Three scenarios were presented: the most conservative considered the “most generous” estimates of appropriateness as per expert opinion; the middle scenario the narrowest over-prescribing definition; the least conservative scenario the “strictest” assumptions of the expert opinion. An inappropriate use of antibiotics was identified in all the scenarios applied, and accounted for 8.8% (most conservative), 15.4% (middle) and 23.1% (least conservative) of the prescriptions analysed. Furthermore, in all included practices there was a proportion of inappropriate prescriptions observed, which ranged from 3.6% to 52.9% (minimum of most conservative and maximum of least conservative scenarios, respectively).

The over-use of antibiotics is a well-documented problem in hospitals and in health-care facilities. Ciofi degli Atti et al 36 conducted annual point prevalence surveys of hospital antibiotic consumption over the period 2008–2016 in the largest children’s hospital in Italy: the prevalence of antibiotic use increased from 42.0% (2008) to 56.2% (2016). A similar trend (from 6.1% in 2008 to 24.2% in 2016) was also observed for the main indication, ie, medical prophylaxis, even though an improvement in the empirical choice of antibiotics was observed. As for misuse in primary care, acute respiratory tract infection is one of the health conditions most strongly related to antibiotic over-use. 37 Bianco et al 27 described the antibiotic prescription pattern for acute respiratory tract infections in a southern Italian setting; results from this study showed that around two-thirds of patients were treated with antibiotics not indicated by guidelines. Consistent with the trend of antibiotic misuse in case of viral or mild bacterial infections, in a large nationwide US managed care network, Shekhawat et al 38 reported approximately 60% of patients diagnosed with acute conjunctivitis received antibiotics.

The problem of self-medication is usually investigated by community surveys that allow for valuable information on antibiotic consumption to be collected, especially for low-income countries. 39 , 40

Haddadin et al 18 conducted a cross-sectional observational study based on a pool of pharmacies in Jordan to investigate the patterns of dispensed antibiotics in terms of appropriateness of drug indications, dosage and duration of treatments over a period of four months from February 2016 to May 2016. The results showed that around one-third of dispensation were without prescription and based on pharmacists’ recommendation or on patients’ request, and the authors speculated that this could be a consequence of the high proportion of people not covered by health-insurance. The 19% of non-prescribed antibiotics were given to patients diagnosed flu or cold, ie, to treat viral infections. Among the prescribed antibiotics dispensed, only 31.5% respected both the correct dosage and treatment duration according to the reference adopted. 41 These data were in line with another cross-sectional study 42 based on a survey submitted to Kuwaiti subjects during the period from January to March 2014, in which 27.5% of the study population have been taking antibiotics without medical consultation and with a recent community-based cross-sectional study conducted in Kemissie town (Ethiopia), in which one-quarter of the respondents did not obtain antibiotics with a prescription. 43 Also a cross-sectional Italian analysis performed in 2011 44 reported that around one-third of the respondents to the survey had taken an antibiotic without the prescription of a physician. A recent scoping review highlighted the self-medication of antibiotics to be highly prevalent among individuals living in low- and middle-income countries. 45 Such medications are often connected with improper use as fever, upper respiratory tract infection, common cold and sore throat. Information about antibiotics were mainly provided by pharmacists or a family member. 45

The duration of antibiotic treatments also plays a crucial role in the development of ABR. While traditionally patients were recommended to complete a full antibiotic course to avoid ABR, a shorter course could be sufficient to treat bacterial infections in outpatient settings, and could represent a reliable strategy to reduce antibiotic consumption and to contrast the increasing rate of ABR. 46 , 47 In this direction were indeed the evidences described by Dawson-Hahn et al 48 in an overview of systemic reviews of randomized controlled trials, that compared the effectiveness of short-courses to long-courses of oral antibiotics. Their findings indicated that for adults and children diagnosed with most common infections (tonsillopharyngitis, acute otitis media, uncomplicated urinary tract infection or mild/moderate community acquired pneumonia) managed in outpatient settings, short course antibiotics were as effective as longer course. The duration of antibiotic therapies as a threat for ABR was also under debate in the context of healthcare associated infections, specifically among the WHO recommendation for the prevention of surgical site infections. 49 Even though guidelines recommend a postoperative duration of 24 hours at maximum, the expert panel advises against such prolongation of surgical antibiotic prophylaxis. This recommendation is based on a metanalysis conducted on 69 RCTs, in which prolonged regimens did not significantly reduce the incidence of surgical site infections compared with a single dose of antibiotic prophylaxis. 49 Moreover, to avoid surgical site infections, the administration of prophylactic antibiotics therapy should cover the most common pathogens of the surgical site (that can be gram-positive or gram-negative bacteria), and should be administered for the short effective period, at a time ensuring an adequate serum concentration. 50

High levels of antibiotic consumption are commonly encountered among residents of long-term care facilities. 51 A population-based study performed in these institutions reported that around half of antibiotics administered had long treatment courses that exceed the “threshold” of one week. 52 Notably, the use of prolonged therapies interested all antibiotic classes, including those for which a shorter duration was evidence-supported.

Administration of antibiotics for the shortest possible duration is one of the simplification regimen principles included in the concept of “antibiotic de-escalation”. The latter is gaining widespread recognition as a key strategy for ABR stewardship. 53 , 54 Briefly, de-escalation consists of modification of the initial broad-spectrum antibiotic therapy with a narrow-spectrum once the culture is available, and discontinuation of antimicrobial treatment if no infection is established. 55 Moreover, de-escalation comprises reduction of the number of antibiotics and optimization of the antibiotic dose and route of administration. 55 Similarly, in the choice of the appropriate empirical therapy for patients at high-risk of surgical site infection, a step-by-step reduction method is applied by administering broad-spectrum antibiotics at first, and adjusting the treatment according to the patient’s response and the results of bacterial identification. 56

ABR Negative Outcomes

The association of ABR with adverse health and economic outcomes is widely documented in literature. 57–60 ABR leads to long-lasting infections and causes a delay in the administration of microbiologically effective therapy. Moreover, due to the limited treatment options, patients affected with these infections may need toxic therapies administration, have prolonged hospitalizations or require surgical procedures. Overall, the impact of ABR results in increased morbidity and higher mortality rate, as well as in an increased resource utilization and higher costs. 58

Clinical Impact

To better describe the population with infections caused by ABR organism and their negative clinical impact, observational studies focusing on different types of infection are presented.

Ryan et al 61 conducted a retrospective study with the aim to investigate the prevalence of ABR bacteria affected by urosepsis and admitted in the emergency department of an Irish hospital between 2016 and 2018. Almost all patients included (97%) reported a gram-negative organism as the causative pathogen. In the study population, a high level of ABR towards commonly prescribed antibiotics and broader agents (22% piperacillin-tazobactam, 18% ciprofloxacin) were observed, underlying the actual challenge of choosing the appropriate therapy for these conditions. Patients from long-term care facilities were two-fold likely to be infected by an ABR organism compared to the community. Furthermore, patients with ABR were characterized as having more co-morbidities such as diabetes, dementia, hypertension and ischaemic heart disease. Due to the relatively small sample size, no statistically significant difference in mortality or in length of hospitalization stays were detected between the resistant and non-resistant cohorts. On the contrary, Huang et al 62 reported in their retrospective analysis that patients with urosepsis caused by extended-spectrum ß-lactamase (ESBL) had a worse prognosis than the ones with non-ESBL urosepsis: the authors found a median length of hospitalization and of treatment duration of 4 days and 1 day longer, respectively. Furthermore, patients with ESBL urosepsis received less frequently the adequate antimicrobial therapy within 24 hours (82.8% ESBL urosepsis vs 94.9% non-ESBL urosepsis, p-value 0.012). Ultimately, resistant patients experienced more frequently all-cause mortality or discharge with palliative measures.

Multidrug-resistant Acinetobacter baumannii (MR-AB) strains have emerged over the past decades as one of the main causes of healthcare associated infections, particularly in intensive care unit. 63 , 64 This pathogen is difficult to treat, and it is associated with high morbidity and mortality. 63 Munier et al 65 reported a prospective study aimed to evaluate the outcomes of MR-AB infection in a Burn Unit (BU) in France during an outbreak that occurred in 2014. MR-AB infections correlated with longer hospitalization stays, regardless of the outcome death/survival: considering only patients discharged alive, median length of hospital stay was 67 days in those MR-AB infected versus 19 days in patients not infected. The evaluation of the cause-specific hazard ratio (CSHR) revealed that MR-AB was associated with an increased risk of death (CSHR: 7.11; 95% CI: 1.52–33.2; p-value 0.013). 57% of the deaths registered among patients with MR-AB was related to such infection, 29% were uncertainly related and 14% were unrelated.

ABR represents a serious issue for all those patients that require continuous hospitalization or that are repeatedly exposed to antibiotics, as in the case of liver cirrhosis. Bartoletti et al 66 performed a large prospective multicentre cohort study on patients with liver cirrhosis who developed bloodstream infections (BSI). One of the main findings of the study concerned the high proportion (31%) of BSI caused by multidrug-resistant organisms (MDRO), and the presence of these pathogens was strongly associated with inadequate empirical therapy and delays (during the first 24 hours) in effective treatment. These two last factors were in turn associated with increased rates of mortality. In addition, antimicrobial exposure or presence of invasive procedures in the 30 days prior BSI onset were identified as possible risk factors for MDRO.

Economic Burden

Economic burden of ABR was extensively reviewed over the past years. 17 , 67–69 From the studies published in the literature, it seems clear that to estimate the costs for ABR is not an easy task, as different methodologies need to be applied, according to the perspective being taken. 17 Costs from the patient perspective refer to associated mortality and morbidity, longer hospitalizations and higher toxic effects of second line drugs; costs from the health-care perspective consider additional diagnostic tests for resistant infection and reduced patient turnover and decreased revenues due to longer hospital admission. 17 , 70 Alongside these perspectives, a secondary societal burden must be contemplated, that refers to the implication of ABR for medical procedure, eg, prophylactics in surgical procedure and antibiotic co-treatments for immunocompromising treatments. 17 , 70

With these premises, Shrestha et al 70 estimated the direct and indirect costs (US $) of ABR (selecting key pathogens) per different classes of antibiotics consumed, using data from a low-middle income (Thailand) and high income (US) country to reproduce the variation in the global burden of ABR. For each resistant infection, direct costs ranged from $9.8 to $29.0 million in Thailand and from $9.5 to $113.8 million in US, while indirect costs spanned from $5 to $56 million and from $97 to $2184 million in Thailand and US, respectively. The total economic cost of ABR due to drug resistance in the pathogens considered was $0.5 billion in Thailand and $2.8 billion in US.

Consistent with these data, the costs estimated in Europe due to ABR per year were estimated to be €1.5 billion ($1.65 billion in US currency) considering health-care costs and productivity losses. 71 According to O’Neill, the cost of taking global action for ABR is up to $40 billion for the next years, little if compared to the $100 trillion estimated as costs of inaction. 6

Finally, a systemic review that evaluated the economic impact of antimicrobial stewardship programs reported a cost-saving mainly related to reduction in antibiotic consumption and direct costs, thus highlighting a potential positive health economic impact that warrant future research to be conducted to get insights also regarding hospitalization length and re-admission rates. 72

To date, several programmes are currently ongoing to tackle the multifaceted health threat of ABR. 73 , 74 Alternative approaches for the treatment of infectious diseases as antibodies, probiotics, vaccine development, phage therapy or small-molecule adjuvants affecting immune cells are in development. 4

This review provided a picture of the magnitude of ABR issue in clinical practice settings reporting population-based analysis/survey. The studies herein mentioned highlighted the misuse of antibiotics as one of the main contributors to ABR growing phenomenon. The misuse of antibiotics is often reported in terms of high consumption, over-prescription of antibiotics, inappropriate prescribing, or self-prescription. Several aspects still need to be addressed to stop ABR from spreading; first of all, further active plans should be put in place to optimize the use of antibiotics also in terms of duration of treatments, and to minimize the over-use and inappropriate use of antibiotics. In this direction, antimicrobial stewardship takes into account decisions concerning the dose and duration of the most appropriate antibiotics to ensure minimal impact on local resistance levels and ensuring their availability and efficacy for the future. In addition, the diagnostic stewardship, ie, the implementation of rapid diagnostic techniques in clinical microbiology laboratories to aid the choice of drug therapy, is another emerging facet of antimicrobial stewardship. 75 Moreover, ABR was associated in different studies with an increased risk of longer hospitalization and mortality. The clinical and economic burdens of ABR are huge and call for antibiotic stewardship programs to be taken and for increasing global surveillance networks.

The authors report no conflicts of interest in this work.

A .gov website belongs to an official government organization in the United States.

A lock ( ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

• Tips for Antibiotic Do's and Don'ts
• Antibiotic Use and Antimicrobial Resistance
• Patient Education Resources
• Clinical Features of Penicillin Allergy
• Clinical Care for Adult and Pediatrics
• Antibiotic Stewardship Trainings
• Antibiotic Use Report
• Educational Materials for Healthcare Providers
• Core Elements of Antibiotic Stewardship
• Antibiotic Stewardship Resource Bundles
• Improving Antibiotic Use in Outpatient Hemodialysis Facilities

Antibiotic Use and Antimicrobial Resistance Facts

At a glance.

• Antibiotics are drugs that kill certain kinds of germs called bacteria and stop their growth.
• Anytime antibiotics are used, they can cause side effects and contribute to antimicrobial resistance (when germs can defeat the drugs designed to kill them).
• Antibiotics aren't always the answer when you're sick. Use antibiotics only when you need them to protect yourself from harms caused by unnecessary antibiotic use and fight antimicrobial resistance.

Antibiotics FAQs

What are bacteria.

Bacteria are germs found inside and outside of our bodies. Most germs are harmless. Some are helpful to humans. However, bacteria can cause infections, like strep throat and urinary tract infections.

What is an antibiotic?

Antibiotics are drugs that kill certain kinds of germs called bacteria and stop their growth. Antibiotics are critical tools for preventing and treating infections caused by specific bacteria in people, animals and crops. In health care, antibiotics are one of our most powerful drugs for fighting life-threatening bacterial infections.

We need antibiotics to treat life-threatening conditions caused by bacteria (e.g., sepsis , the body's extreme response to infection).

What is a virus?

Viruses are germs different from bacteria. They cause infections, such as colds and flu. However, antibiotics do not treat infections caused by viruses .

Appropriate antibiotic use

It's important we use antibiotics only when it is necessary.

What is unnecessary antibiotic use?

Unnecessary antibiotic use happens when a person takes antibiotics they don't need, like for colds and flu. Unnecessary use also happens when a person takes antibiotics for infections that are sometimes caused by bacteria that do not always need antibiotics, like many sinus infections and some ear infections.

What is misuse of antibiotics?

Misuse of antibiotics happens when a person takes the wrong antibiotic, the wrong dose of an antibiotic or an antibiotic for the wrong length of time. Talk to your doctor about the best treatment for your illness and steps you can take to feel better when you don't need an antibiotic. Never pressure your doctor to prescribe an antibiotic. Do not save antibiotics for later.

Antimicrobial resistance

What is antimicrobial resistance.

Antimicrobial resistance happens when germs like bacteria and fungi develop the ability to defeat the drugs designed to kill them. That means the germs continue to grow.

Resistant infections can be difficult, and sometimes impossible, to treat. Bacteria and fungi do not have to be resistant to every antibiotic or antifungal to be dangerous. Resistance to even one antibiotic can mean serious problems. Antimicrobial resistance can affect any person, at any stage of life.

Antimicrobial resistance does not mean our body is resistant to antibiotics or antifungals.

Why should I care about antimicrobial resistance?

Did you know‎.

Infections caused by antimicrobial-resistant germs can be difficult, and sometimes impossible, to treat. In many cases, antimicrobial-resistant infections require extended hospital stays, follow-up doctor visits and costly and toxic alternative treatments. People receiving health care or those with weakened immune systems are often at higher risk for getting an infection, including antimicrobial-resistant infections. When we need antibiotics, the benefits usually outweigh the risks of antimicrobial resistance. However, too many antibiotics are being used unnecessarily and are misused, which threatens the effectiveness of these important drugs.

Many medical advances are dependent on the ability to fight infections using antibiotics, including joint replacements, organ transplants, cancer therapy, and the treatment of chronic diseases like diabetes, asthma, and rheumatoid arthritis. If antibiotics and antifungals lose their effectiveness, then we lose the ability to treat infections and control these public health threats.

Aside from health care , antimicrobial resistance also impacts the veterinary and agriculture industries.

Protect yourself and your family

Everyone has a role to play in improving antibiotic use. Taking antibiotics when needed is an important way you can protect yourself and your family and help combat antimicrobial resistance.

There are steps you can take to protect yourself and your family from infections caused by antimicrobial-resistant germs.

Learn about other ways to stay safe and healthy while taking antibiotics .

What's being done

• CDC's report Antibiotic Resistance Threats in the United States, 2019
• COVID-19 and Antimicrobial Resistance
• 2023 Stewardship Report

Antibiotic Prescribing and Use

Antibiotics can save lives, but any time antibiotics are used, they can cause side effects and contribute to the development of antibiotic resistance.

For Everyone

Health care providers, public health.

A mother’s loss launches a global effort to fight antibiotic resistance

• Show more sharing options
• Copy Link URL Copied!

In November 2017, days after her daughter Mallory Smith died from a drug-resistant infection at the age of 25, Diane Shader Smith typed a password into Mallory’s laptop.

At this point, keeping myself alive is a full-fledged mission, enlisting all of my energy and hours every day. I need to fight the chronic deadly resistant bacteria eating away at my fragile, scarred lungs. Fight the billions of bacteria overtaking my lungs and clear out the mucus so I don’t feel like I’m breathing through a straw with a boulder weighing on my chest.

— Mallory Smith, Oct. 16, 2014

Her daughter gave it to her before undergoing double-lung transplant surgery, with instructions to share any writing that could help others if she didn’t survive.

Had this idea today that I wanted to write down before it leaves my mind or I stop feeling inspired or I forget it or something inside me tells me it’s not possible. I want to start an online media source (podcast? website?) that tells the stories of people who have struggled with something in their life and found hope somewhere.

— Mallory Smith, July 20, 2015

The transplant was successful, but Burkholderia cepacia — an antibiotic-resistant bacterial strain that first colonized her system when she was 12 — took hold. After a lifetime with cystic fibrosis, and 13 years battling an unconquerable infection, Mallory’s body could take no more.

Cepacia has taken over, and it’s time to figure out a transplant option. I realize I want to write my story.

— Mallory Smith, July 29, 2016

In the haze of grief and pain, Shader Smith found herself looking through 2,500 pages of a journal her daughter had kept since high school. It chronicled Mallory’s hopes and triumphs as an ebullient, athletic student at Beverly Hills High School and Stanford University, and her private despair as bacteria ravaged her systems and sapped her considerable strength.

In the years since, the journal has become a source of solace for Shader Smith as she has traveled the globe speaking about the growing threat of antimicrobial resistance. It is also now the inspiration for two new projects she hopes will spark greater understanding of the public health crisis that ended her daughter’s life prematurely and could claim millions more.

On Tuesday, Random House published “Diary of a Dying Girl,” a selection of Mallory’s journal entries. The same day saw the launch of the Global AMR Diary , a website collecting the worldwide stories of people battling pathogens that can’t be defeated by our current pharmaceutical arsenal.

An estimated 35,000 people die in the U.S. each year from drug-resistant infections, according to the U.S. Centers for Disease Control and Prevention. Worldwide, antimicrobial resistance kills an estimated 1.27 million people directly every year and contributes to the deaths of millions more.

Despite the mounting toll — and the prospect of an eventual surge in superbug fatalities — the development of new antibiotics has stagnated.

Shader Smith is acutely aware of what we stand to lose when medicine can no longer save us.

“I don’t want to live in a post-antibiotic world,” Shader Smith said. “Until people understand what’s at stake, they’re not going to care. My daughter died from this. So I care deeply.”

Over the last 50 years, opportunistic pathogens have evolved defenses faster than humans can develop drugs to combat them.

Misuse of antibiotics has played a large part in this imbalance. Bugs that survive antibiotic exposure pass on their resistant traits, leading to hardier strains.

Crucial as they are, antibiotics don’t have the same financial incentives for developers that other drugs do. They aren’t meant to be taken over the long term, as are medications for chronic conditions such as diabetes or high blood pressure. The most powerful ones have to be used as rarely as possible, to give bacteria fewer opportunities to develop resistances.

“The public does not understand [the] scope of the problem. Antimicrobial resistance truly is one of the leading public health threats of our time,” said Emily Wheeler , director of infectious disease policy at the Biotechnology Innovation Organization. “The pipeline for antibiotics today is already inadequate to address the threats that we know about, without even considering the continuous evolution of these bugs as the years go on.”

Science & Medicine

Could a single synthetic molecule outsmart a variety of drug-resistant bacteria?

Scientists have created a synthetic molecule that appears capable of attacking a broad range of bacteria that have become dangerously resistant to workhorse medicines.

Feb. 15, 2024

Despite the global nature of the threat, Shader Smith said, the response from public health officials is curiously disjointed.

For one, no one can agree on a single name for the problem, she said. Different agencies address the issue with an “alphabet soup” of acronyms: the World Health Organization uses AMR as shorthand for antimicrobial resistance, while the CDC prefers AR. Medical journals, doctors and the media refer alternately to multidrug resistance (MDR), drug-resistant infections (DRI) and superbugs.

“It doesn’t matter what you call it. We just have to all call it the same thing,” said Shader Smith, who works as a publicist and marketing consultant.

Since Mallory’s death, Shader Smith has made it her mission to get the people and organizations working on antimicrobial resistance to talk to one another. For the Global AMR Diary, she enlisted the help of a dozen agencies working on the issue, including the CDC, WHO, the European Center for Disease Prevention and Control (the European Union’s equivalent of the CDC), the Biotechnology Innovation Organization and others.

Antimicrobial resistance can “feel abstract given the scale of the problem,” said John Alter, head of external affairs of the AMR Action Fund , one of the organizations involved with the project. “To know there are millions of families at this very moment going through struggles similar to what Mallory experienced is simply unacceptable,” he said.

“Not only does this firsthand experience help others who might be going through something similar, but it also reminds those tasked with creating solutions and care who they are working for. They aren’t just test tubes or charts,” said Thomas Heymann, chief executive of Sepsis Alliance , another contributor.

A potent antibiotic has emerged in the battle against deadly, drug-resistant superbugs

For the first time in half a century, researchers have identified a new antibiotic that appears to kill a deadly, drug-resistant superbug.

Jan. 3, 2024

The stories in the online diary are often harrowing. A 25-year-old pharmacist in Athens had to put her cancer treatment on hold when an extremely resistant strain of Klebsiella attacked . A veterinarian in Kenya suffered permanent disability after contracting resistant bacteria after hip surgery. Around the world, routine outpatient procedures and illnesses have rapidly become life-threatening when opportunistic bugs take hold.

Mallory was 12 when her doctor called to confirm that her cultures were positive for an extremely resistant strain of cepacia , a form of bacteria found widely in soil and water. The pathogen can be deadly to people with underlying conditions such as cystic fibrosis, a genetic disorder that impairs the cells’ ability to effectively flush mucus from the lungs and other body systems.

Life expectancies for people with cystic fibrosis have grown since Mallory’s diagnosis in 1995, with many people of them living into their 40s and beyond. The cepacia curtailed that possibility for her.

“This is all we’re ever going to have,” Mallory wrote in June 2011, at the end of her freshman year at Stanford, “so if you’re not actively pursuing happiness then you’re insane. And I don’t think I would have this perspective if I didn’t have resistant bacteria that will likely kill me.”

A shrine to Mallory Smith. She fought a drug-resistant bacteria from age 12 to 25, all through high school, then at Stanford. (Genaro Molina / Los Angeles Times)

Mallory’s intuition that her journal could be valuable to others was prescient. “People can easily understand and relate to actual experiences,” said Michael Craig, director of the CDC’s Antimicrobial Resistance Coordination and Strategy Unit. “The Global AMR Diary takes this approach and expands on it with a global lens — increasing the potential to get these critical messages to more people around the world.”

An earlier version of Mallory’s diaries was published in 2019 as “ Salt in My Soul: An Unfinished Life .” The new book includes entries that Shader Smith said she wasn’t ready to grapple with in the immediate aftermath of Mallory’s passing: ones addressing depression and private despair, concerns about relationships and body image issues complicated by chronic illness.

It also includes a coda about phage therapy, a promising advance against AMR.

As cepacia overwhelmed Mallory’s system in the weeks after her transplant, her family secured an experimental dose of phage therapy. Widely used to treat infection before the advent of antibiotics, phages are viruses that destroy specific bacteria. The treatment arrived too late to save Mallory’s life, Shader Smith writes in a last chapter of the book, but her autopsy revealed that the phages had started to work as intended.

The systems that bring new drugs to patients move slowly, Shader Smith said, and “Mallory might have been saved if they had moved faster.” Her mission now is to make sure that they do.

“Mallory died six years ago. Six years is a long time, day in and day out,” she said. “And I’ve never taken my foot off the pedal.”

‘Miracle’ weight-loss drugs could have reduced health disparities. Instead they got worse

Ozempic and other drugs raised the possibility of reversing the country’s obesity crisis. Doctors are frustrated that they’ve made health disparities worse.

April 15, 2024

Corinne Purtill is a science and medicine reporter for the Los Angeles Times. Her writing on science and human behavior has appeared in the New Yorker, the New York Times, Time Magazine, the BBC, Quartz and elsewhere. Before joining The Times, she worked as the senior London correspondent for GlobalPost (now PRI) and as a reporter and assignment editor at the Cambodia Daily in Phnom Penh. She is a native of Southern California and a graduate of Stanford University.

More From the Los Angeles Times

Climate & Environment

Cloudy with a chance of rage: Climatologists fume over relocation of L.A. weather station

May 17, 2024

California is changing how big power companies charge for electricity. What to expect on your bill

May 16, 2024

Travel & Experiences

The 101 best West Coast experiences

This anesthesiologist is L.A. County’s highest paid employee. He works 94 hours a week

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• My Account Login
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• Review Article
• Open access
• Published: 08 June 2023

Antibiotics in the clinical pipeline as of December 2022

• Mark S. Butler   ORCID: orcid.org/0000-0001-6689-4236 1 ,
• Ian R. Henderson   ORCID: orcid.org/0000-0002-9954-4977 1 ,
• Robert J. Capon   ORCID: orcid.org/0000-0002-8341-7754 1 &
• Mark A. T. Blaskovich   ORCID: orcid.org/0000-0001-9447-2292 1  

The Journal of Antibiotics volume  76 ,  pages 431–473 ( 2023 ) Cite this article

24k Accesses

41 Citations

113 Altmetric

Metrics details

• Drug discovery
• Microbiology

A Correction to this article was published on 07 November 2023

This article has been updated

The need for new antibacterial drugs to treat the increasing global prevalence of drug-resistant bacterial infections has clearly attracted global attention, with a range of existing and upcoming funding, policy, and legislative initiatives designed to revive antibacterial R&D. It is essential to assess whether these programs are having any real-world impact and this review continues our systematic analyses that began in 2011. Direct-acting antibacterials (47), non-traditional small molecule antibacterials (5), and β-lactam/β-lactamase inhibitor combinations (10) under clinical development as of December 2022 are described, as are the three antibacterial drugs launched since 2020. Encouragingly, the increased number of early-stage clinical candidates observed in the 2019 review increased in 2022, although the number of first-time drug approvals from 2020 to 2022 was disappointingly low. It will be critical to monitor how many Phase-I and -II candidates move into Phase-III and beyond in the next few years. There was also an enhanced presence of novel antibacterial pharmacophores in early-stage trials, and at least 18 of the 26 phase-I candidates were targeted to treat Gram-negative bacteria infections. Despite the promising early-stage antibacterial pipeline, it is essential to maintain funding for antibacterial R&D and to ensure that plans to address late-stage pipeline issues succeed.

Similar content being viewed by others

The global preclinical antibacterial pipeline

Antibiotics in the clinical pipeline in October 2019

Critical analysis of antibacterial agents in clinical development

Introduction.

Antibiotics are the foundation of modern medicine but are becoming increasingly ineffective due to growing levels of antimicrobial resistance, threatening global health. The adverse impact of drug-resistant infections is highlighted by a seminal analysis of the global burden of bacterial antimicrobial resistance in 2019, with 1.27 million deaths directly attributed to, and 4.9 million deaths associated with, resistant bacteria [ 1 ]. The development of new antibiotics, particularly new chemotypes or classes that can overcome existing resistance mechanisms, has been hindered by a failure of the healthcare system marketplace to adequately recognize and compensate for these products [ 2 , 3 , 4 ]. In addition to improved generic antibiotic sales, branded antibiotic prices have fallen since 2001 [ 5 ], aggravating the economic challenges. Recognition of the antibiotic crisis has led to the establishment of targeted funding initiatives for antibiotic development such as the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) [ 6 ], INCATE [ 7 ], REPAIR Impact Fund [ 8 ], and the AMR Action Fund [ 9 , 10 ], testing of new incentives to reimburse pharmaceutical companies such as a subscription ‘Netflix’ model [ 11 , 12 , 13 , 14 ], and legislative initiatives such as the PASTEUR (The Pioneering Antimicrobial Subscriptions To End Up surging Resistance) Act in the United States [ 15 , 16 ]. There has also been an increase in the number of “non-traditional” antibacterials [ 17 , 18 , 19 , 20 , 21 ] being actively evaluated in clinical trials [ 21 , 22 ]. Non-traditional antibacterials can be small molecules, monoclonal antibodies (mAbs), proteins or live biotherapeutics such as bacteria and bacteriophages that primarily affect bacteria growth or virulence indirectly with varying mechanisms such as toxin binding, cell adherence reduction, inhibition of antivirulence targets and drug resistance modification [ 21 ].

To assess whether these activities are improving the status quo, we have monitored antibacterial drug development since 2011 with reviews published in 2019 [ 23 ], 2015 [ 24 ], 2013 [ 25 ] and 2011 [ 26 ]. Complementary reviews with different approaches and analyses (but often with few or no chemical structures) are available. The Pew Trusts developed an online pipeline tracker that allows the visualization of changes in the pipeline from 2014–2020 [ 27 ], but their antibiotic resistance project was discontinued in December 2021 [ 28 ]. In 2022, the WHO published a report on antibacterial agents in both preclinical and clinical development in 2021 [ 22 ] and a journal article in 2022 [ 21 ]. The WHO also recently reviewed the preclinical and clinical antibacterial vaccine pipeline [ 29 ]. A 2021 review critically analyzed why compounds with Gram-negative (G-ve) activity have fallen out of the pipeline over the past decade [ 30 ], while two 2020 reviews covered both the clinical [ 31 ] and preclinical [ 32 ] antibacterial pipelines, with a third providing an overview of ‘novel’ antibacterial agents in various stages of development [ 33 ]. Reviews of patents from 2010–2021 focusing on compounds with activity against multi-drug resistant (MDR) G-ve bacteria [ 34 ], antibacterial combinations [ 35 ], and discovery strategies [ 36 ] have also been published.

This review catalogs the small molecule antibacterial drugs launched since January 2012 in Table  1 and the yearly number of first-time antibacterial drugs launched by year since 2000 (Fig.  1 , Table  S1 ). International Nonproprietary Names (INN) are used for compound names when available. For completeness, Table  2 lists the non-traditional antibacterial drugs launched during this period. The new antibacterial drugs approved since the previous 2019 review [ 23 ], levonadifloxacin ( 1 ) and its prodrug alalevonadifloxacin ( 2 ), and contezolid ( 4 ) (Fig.  2 ), are analyzed. Consistent with previous reviews in this series [ 23 , 24 , 25 , 26 ], small molecule antibacterials (both traditional and non-traditional) and β-lactamase/β-lactam inhibitor (BL/BLI) combinations that are being evaluated in phase-I, -II, or -III clinical trials and under pre-approval regulatory evaluation as of 31 December 2022 are summarized (Tables  3 – 6 , Figs.  3 – 13 ), along with their development status, mode of action (MoA), spectra of activity, historical discovery, and lead compound origin (natural product (NP), synthetic (S) or protein/mammalian peptides (P)). In the previous 2019 review [ 23 ], one antibody drug conjugate (ADC), DSTA4637S, was discussed, but its development has since been halted (Table  7 ). The clinical trial study codes, which are predominantly from ClinicalTrials.gov (NCT), are listed in parentheses for each trial, while non-registered trials are referenced at least in a Press Release or peer-reviewed publication. An overview of the drug development and approval process, on-line clinical trial databases antibiotic clinical trial categories and abbreviations can be found in the  Supplementary Information . Prodrugs are grouped together with their active metabolites, while ongoing trials of antibacterial drugs already approved anywhere in the world are presented in Table  S2 . Compounds where no development activity has been identified since 2018 are listed in Table  7 . The antibacterials in clinical development have been further analyzed by phase and source derivation (Fig.  14 ) and also compared with data reported in our 2011 [ 26 ], 2013 [ 25 ], 2015 [ 24 ] and 2019 [ 23 ] reviews (Fig.  15 ). An analysis of new antibacterial pharmacophores (Table  8 , Figs.  16 and 17 ) and administration routes (Figs.  S1 and S2 ) is also included. The administration routes in this review are as follows: po (oral), IV/po (intravenous oral switch); IV (intravenous), IV/topical (IV and topical), po topical (orally administered for  Clostridioides difficile (formally Clostridium [ 37 ]) infections (CDI)), oral, topical and inhalation. The ‘po topical’ term distinguishes between oral administration to treat C. difficile infections and the gut microbiome compared to topical administration via creams, sprays, and eyedrops.

New small molecule antibacterial drugs and BL/BLI combinations launched from January 2000 to December 2022 with new classes highlighted

Structures of the recently lauched antibacterial drugs

Structure of the antibacterial in the NDA and MAA development stage (Table  3 )

Structures of compounds in phase-III clinical trials (Table  3 )

Structures of NP-derived compounds in phase-II clinical trials (Table  4 )

Structures of synthetic compounds in phase-II clinical trials (Table  4 )

Structures of small molecule non-traditional antibacterials in phase-II clinical trials (Table  4 )

Structures of NP and peptide-derived compounds in phase-I clinical trials (Table  5 )

Structures of synthetic-derived compounds in phase-I clinical trials (Table  5 )

Structures of publicly disclosed small molecule non-traditional antibacterials in phase-I clinical trials (Table  5 )

Structures of BLI and associated β-lactam antibacterial in NDA/MAA filing (Table  6 )

Structures of BLIs in phase-III clinical trials (Table  6 )

Structures of BLIs and associated β-lactam antibiotics in phase-I clinical trials (Table  6 )

Compounds under clinical evaluation divided into development phases and their lead derivation source: natural product (NP) (NP-derived and NP-BLI), protein/mammalian peptide (P-derived) and synthetic (S) (S-derived and S-BLI)

Comparison of the numbers of compounds undergoing clinical development as of 2011 [ 26 ], 2013 [ 25 ], 2015 [ 24 ], 2019 [ 23 ] and 2022 by development phase

Antibacterial compounds [natural product (NP), synthetic (S), protein/mammalian peptide (P)] and β-lactamase inhibitors (BLI)] with new antibacterial pharmacophores divided into development phases and their lead derivation source

Comparison of the numbers of novel antibacterial pharmacophores undergoing clinical development in 2011 [ 26 ], 2013 [ 25 ], 2015 [ 24 ], 2019 [ 23 ] and 2022 by development phase

Data in this review were obtained by analyzing the scientific literature and internet sources such as company and funding organization websites, clinical trial registers, The Pew Charitable Trusts (Philadelphia, PA, USA) [ 28 ] and World Health Organization (WHO) (Geneva, Switzerland) pipeline analyses [ 21 , 22 ] and biotechnology newsletters. Every effort has been made to ensure the accuracy of this data; however, it is possible that compounds in the early stages of clinical development have been overlooked as there is limited information available in the public domain.

Antibacterial drugs launched from January 2013 to December 2022

In the last 10 years, 19 new small molecule antibacterial drugs (eight NP-derived and 11 synthetic-derived) and four new BL/BLI combinations have been approved (Table  1 and S1 , Figs.  1 and 2 ). Among these 19 antibacterial drugs, none was first-in-class, with the last being bedaquiline in 2012 (diarylquinoline class), which also was the first new tuberculosis (TB) drug class since 1963 [ 38 ]. Although the semi-synthetic pleuromutilin derivative lefamulin was approved in 2019 for systemic use for community-acquired bacterial pneumonia (CABP) infection, a topically administered pleuromutilin, retapamulin, was approved in 2007. While new classes of G-ve antibacterial drugs have been approved, new exemplars within existing classes, especially BL/BLI combinations, also show improved activity profiles against resistant G-ve bacteria.

Since the 2019 review [ 24 ] in this series, two new small molecule antibacterials (Table  1 , Figs.  1 and 2 ), levonadifloxacin ( 1 ) (as its prodrug alalevonadifloxacin ( 2 )) and contezolid ( 4 ) were first approved in India and China respectively.

Levonadifloxacin ( 1 ) (Emrok, WCK-771; IV), which is the arginine salt of the fluoroquinolone S -(–)-nadifloxacin, and its alanine prodrug alalevonadifloxacin ( 2 ) (Emrok O, WCK-2349; po) [ 39 , 40 , 41 ] were developed by Wockhardt (Mumbai, Republic of India). Both the IV and oral formulations were approved in January 2020 by the Indian Central Drugs Standard Control Organization (CDSCO) for the treatment of acute bacterial skin and skin structure infections (ABSSSI), including diabetic foot infections and concurrent bacteremia [ 42 , 43 ]. Levonadifloxacin ( 1 ) has activity against G+ve bacteria including MRSA, as well as some G-ve bacteria [ 41 ], and a prescription-event monitoring study was recently published [ 44 ]. Racemic nadifloxacin was first approved in 1993 to topically treat acne and MRSA infections [ 45 ].

Contezolid ( 4 ) (Youxitai, MRX-1; IV) is an oxazolidinone developed by MicuRx Pharmaceuticals (Hayward, CA, USA and Shanghai, People’s Republic of China). It was approved by the Chinese National Medical Products Administration (NMPA) in June 2021 for the treatment of complicated skin and soft tissue infections (cSSTI), including, but not limited to, MSSA, MRSA, Streptococcus pyogenes and Streptococcus agalactiae [ 46 , 47 , 48 ]. The development pathway from contezolid ( 4 ) [ 49 ] to contezolid acefosamil ( 3 ) (MRX-4) was recently published [ 50 ]. The prodrug 3 provides dramatic improvements in solubility over the parent antibiotic (from 0.2 mg ml −1 to >200 mg ml −1 ), leading to exposure of contezolid ( 4 ) in rats after IV administration of contezolid acefosamil ( 3 ) like, or higher than, that from direct IV administration of 4 . A phase-III trial (NCT05369052) evaluating contezolid acefosamil ( 3 ) (po)/contezolid ( 4 ) (IV) for diabetic foot infections compared to linezolid began in May 2022.

Three non-traditional antibacterial drugs (two mAbs and one biotherapeutic) were launched between 2013 and 2022 to treat bacterial infections (Table  2 ), compared to 19 traditional antibacterial drugs launched during this period (Table  1 ).

Obiltoxaximab [ 51 , 52 ] is a mAb that neutralizes harmful toxins produced by Bacillus anthracis that was approved using the US FDA Animal Rule based on their efficacy in relevant animal models and safety in phase-I studies. Another mAb that also neutralizes B . anthracis toxins, raxibacumab [ 52 , 53 ], was similarly approved in 2012. The mAb bezlotoxumab, which binds to toxin B produced by C. difficile [ 54 , 55 ], was approved in 2016 to help prevent the recurrence of CDI after successfully completing two phase-III trials [ 56 , 57 ].

In November 2022, a live biotherapeutic product, RBX2660 (Rebyota), was approved by the US FDA [ 58 ] to help prevent CDI following antibiotic treatment, based on phase-III trial data [ 59 ]. RBX2660 is a liquid suspension donor fecal microbiota that has been screened for bacterial, viral and parasitic pathogens [ 60 , 61 ] that was developed by Rebiotix Inc (Roseville, MN, USA), which is part of Ferring Pharmaceuticals (Saint-Prex, Switzerland). There is also another phase-III trial (NCT03931941) in progress.

Although outside the cut-off period, another non-traditional antibacterial product, Vowst (SER-109), developed by Seres Therapeutics Inc (Cambridge, MA, USA) and Nestlé Health Science (Hoboken, NJ, USA) was approved by the US FDA on 26 April 2023. Footnote 1

Compounds undergoing clinical evaluation

Direct acting small molecules, mammalian-derived peptides and polymeric compounds currently undergoing clinical trials or under regulatory evaluation for the treatment of bacterial infections on 31 December 2022 are detailed in the following tables and figures: NDA and phase-III in Table  3 and 6 with structures in Figs.  3 , 4 , 11 , and 12 , phase-II in Table  4 with structures in Figs.  5 – 7 , and phase-I in Tables  5 and 6 with structures in Figs.  8 – 10 and 13 . Non-traditional antibacterial candidates that are not small molecules such as biotherapeutic microbiome modulation, phage therapy, and antibodies have not been included in this review.

Compounds in NDA/MAA filing (Table  3 , Fig.  3 )

Solithromycin ( 5 ) (T-4288, CEM-101; IV/po) is a semi-synthetic 2-fluoroketolide [ 62 ] that is being developed by FUJIFILM Toyama Chemical Co., Ltd. (Tokyo, Japan). In April 2019, an NDA was submitted to the Japanese Pharmaceuticals and Medical Devices Agency (PDMA) for use of 5 as a treatment for otorhinolaryngological bacterial infections. Although there have been no subsequent updates, 5 is still listed on their November 2022 pipeline as ‘NDA filing’ for otorhinolaryngology and as phase-III for respiratory infectious disease [ 63 ]. Solithromycin ( 5 ) was previously being developed in the USA and Europe for CABP but development was halted in 2016 and 2017 respectively [ 64 ].

Compounds in phase-III trials (Table  3 , Fig.  4 )

Sulopenem ( 6 ) (CP-70,429), which is a synthetic thiopenem BL first developed by Pfizer (New York, NY, USA) in the 1990s [ 65 , 66 , 67 , 68 ], and its prodrug sulopenem etzadroxil ( 7 ) (PF-03709270; po) are being developed as treatments for G-ve infections by Iterum Therapeutics (Dublin, Ireland). To date, three phase-III trials have been completed and have reported results: complicated intra-abdominal infections (cIAI) (NCT03358576), cUTI (NCT03357614) [ 69 ] and uUTI (NCT03354598) [ 70 ]. In November 2020, Interim filed an NDA for uUTIs with the FDA [ 71 ] for orally administered sulopenem etzadroxil ( 7 ) in combination with probenecid ( 8 ) [ 72 ]. Probenecid ( 8 ) is a marketed drug for gout and hyperuricemia that increases uric acid production, which inhibits BL tubular renal secretion that leads to a longer antibiotic half-life and higher serum concentrations [ 73 ]. However, the FDA issued a Complete Response Letter (CRL) in July 2021 that indicated that the NDA was not approvable in its present form [ 74 ]. In response to this CRL, Iterum initiated another phase-III trial (NCT05584657) in October 2022 to investigate sulopenem etzadroxil ( 7 ) + probenecid ( 8 ) compared to amoxicillin + clavulanic acid for uUTI, which is scheduled to finish in March 2024.

Nafithromycin ( 9 ) (WCK 4873; po) is an orally bioavailable ketolide being developed by Wockhardt Limited (Mumbai, Republic of India) that is being evaluated in a phase-III trial (CTRI/2019/11/021964) in India as an oral treatment for CABP. Nafithromycin ( 9 ) has broad spectrum antibacterial activity against G+ves such as S. pneumoniae and S. aureus and G-ves such as Haemophilus influenzae , Moraxella catarrhalis , Legionella pneumophila , Mycoplasma pneumoniae and Chlamydophila pneumoniae [ 75 , 76 , 77 , 78 ].

Gepotidacin ( 10 ) (GSK-2140944; po) is a new chemotype bacterial Type II topoisomerase inhibitor [ 79 ] (new triazaacenaphthylene class) being developed by Glaxo-SmithKline (GSK) (London, UK) for uUTI and gonorrhea. In November 2022, GSK announced that two phase-III trials (NCT04020341 and NCT04010539) for cUTI were stopped early for efficacy (positive news!), with an NDA planned for the first half of 2023 [ 80 ]. Gepotidacin ( 10 ) is also being evaluated in another cUTI phase-III trial with Japanese participants (NCT05630833), as well as a phase-III trial against uncomplicated urogenital gonorrhea caused by Neisseria gonorrhoeae (NCT04010539). Gepotidacin ( 10 ) has activity against a range of both G+ve and G-ve pathogens [ 81 , 82 , 83 ], including Mycobacteria [ 84 ], Stenotrophomonas maltophilia [ 85 ], Mycoplasma and Ureaplasma [ 86 ].

Zoliflodacin ( 11 ) (ETX0914, AZD0914; po) is another new chemotype topoisomerase inhibitor [ 87 ] (new spiropyrimidinetrione class) being developed by Entasis Therapeutics (Waltham, MA, USA), which was recently acquired by Innoviva (Burlingame, CA, USA) [ 88 ]. Zoliflodacin ( 11 ) is being evaluated in a phase-III trial (NCT03959527) as an oral treatment for uncomplicated gonorrhea [ 89 , 90 , 91 ] in partnership with the Global Antibiotics Research and Development Partnership (GARDP) (Geneva, Switzerland). GARDP has the right to register and commercialize 11 in low- and middle-income countries [ 92 ]. Zoliflodacin ( 11 ) also has activity against Mycoplasma genitalium , which could broaden its effectiveness as a treatment for sexually transmitted infections [ 93 ].

Benapenem ( 12 ) (IV) is a carbapenem that completed a phase-II/III trial in May 2020 (NCT04505683) as an intravenous treatment for cUTI, including pyelonephritis, by Sihuan Pharmaceutical (Beijing, People’s Republic of China). Benapenem ( 12 ) is structurally related to ertapenem and has a similar extended human half-life of 7 h, which supports once-daily IV dosing like ertapenem, an advantage over other carbapenems that require multiple daily dosing due to shorter half-lives [ 94 , 95 ].

Epetraborole ( 13 ) (GSK2251052, AN3365, and BRII-658; po) is a benzoxaborole leucyl-tRNA synthetase (LeuRS) inhibitor [ 96 ], which is a new antibacterial target, being evaluated by AN2 Therapeutics (Menlo Park, CA, USA) in a phase-II/III (NCT05327803) against treatment-refractory Mycobacterium avium complex (MAC) lung disease. MAC accounts for up to 85% of non-tuberculosis mycobacteria (NTM) related lung disease [ 97 ]. Epetraborole ( 13 ) has also been reported to have in vivo activity against Mycobacterium abscessus , another NTM involved in lung infections [ 98 , 99 ]. Epetraborole ( 13 ) was originally developed as a treatment for G-ve infections in phase-II trials for cUTI (NCT01381549) and cIAI (NCT01381562) but these studies were halted due to resistance developing in patients during the cUTI trial [ 100 ]. Brii Biosciences (Durham, NC, USA and Shanghai, People’s Republic of China) have licensed 13 for development in the Greater China region [ 101 ].

Traditional antibacterial compounds in phase-II trials (Table  4 , Figs.  5 and 6 )

Sanfetrinem cilexetil ( 14 ) (GV-104326; po) is a 1-(cyclohexyloxycarbonyloxy)ethyl ester prodrug of the trinem (tricyclic carbapenem) sanfetrinem ( 15 ) first developed in the 1990s by Glaxo Wellcome, which is now part of GSK (London, UK). Sanfetrinem ( 15 ) is active against a range of G+ve (e.g., S. aureus , S. pneumoniae and H. influenzae ) and G-ve bacteria (e.g., E. coli , M. catarrhalis ) [ 102 , 103 , 104 ]. Although sanfetrinem cilexetil ( 14 ) successfully completed a phase-II trial for respiratory infections in 1999, no further development work was undertaken until GSK started a phase-II trial (NCT05388448) in May 2022, which is evaluating 14 against rifampicin-susceptible pulmonary TB [ 105 ]. There has been a recent surge in interest in investigating carbapenem-type antibacterials as TB treatments, as evidenced by TASK (Cape Town, South Africa) leading a study that showed meropenem ( 66 ) in combination with amoxicillin + clavulanic acid had efficacy in a phase-II TB trial (NCT02349841) [ 106 ], as well as a consortium of private and public organizations that screened approximately 8,900 carbapenems against Mycobacterium tuberculosis (Mtb) [ 107 ].

MGB-BP-3 ( 16 ) (po topical) is a DNA binding antibacterial being developed by MGB Biopharma (Glasgow, UK) that successfully completed a phase-II trial (NCT03824795) in May 2020 for the treatment of C. difficile -associated diarrhea (CDAD) [ 108 ]. MGB-BP-3 ( 16 ) was discovered at the University of Strathclyde (Glasgow, UK) and was inspired by the actinomycetes-derived minor groove binders, distamycin, netropsin and thiazotropsin [ 109 , 110 ]. In addition to activity against C. difficile , 16 has activity against a range of G+ve bacteria including S. aureus and Enterococcus faecalis but is not active against G-ve bacteria due to a lack of intracellular accumulation [ 111 ]. It was shown that two molecules of 16 bound to the minor groove of dsDNA, which then interfered with transcription, the supercoiling action of gyrase, and the relaxation and decatenation by topoisomerase IV enzymes in vitro [ 111 ]. This is mechanistically distinct from fluoroquinolones that cause an increase in double strand breaks, as well as induce recA and lexA SOS responses. A preprint has reported that 16 also binds to and inhibits multiple essential promoters on the S. aureus chromosome [ 112 ]. Furthermore, 16 is equally effective against ciprofloxacin-resistant and ciprofloxacin-susceptible strains [ 113 ].

Exeporfinium chloride ( 17 ) (XF-73; topical) is a photosensitizing porphyrin derivative with broad-spectrum G+ve activity [ 114 , 115 , 116 ] and a low propensity for developing resistance [ 117 ] being developed by Destiny Pharma (Brighton, UK). Exeporfinium chloride ( 17 ) successfully completed a phase-II trial (NCT03915470) in March 2021 that investigated its activity against nasal S. aureus in patients at risk of post-operative infections. Destiny Pharma plans to start two phase-III nasal decolonization trials in 2024 after securing a partnering deal [ 118 ].

Synthetic cannabidiol ( 18 ) (CBD, BTX 1801; topical) has been evaluated in a phase-II trial (ACTRN12620000456954) by Botanix Pharmaceuticals (Perth, Australia) for the clearance of nasally colonized S. aureus , as well as in phase-II trials in acne (BTX 1503, NCT03573518) and atopic dermatitis (BTX 1204, NCT03824405). Cannabidiol ( 18 ) is the major non-psychoactive component of cannabis ( Cannabis sativa and C. indica ) and its G+ve antibacterial activity, along with that of the major psychoactive compound Δ 9 -tetrahydrocannabinol, was reported as having potential as a topical antibacterial in 1976 [ 119 ]. Anti-MRSA activity of 18 was later confirmed in 2008 [ 120 ] and 2020 [ 121 ] studies, along with other analogs. In 2021, an in-depth study showed that 18 was active against drug resistant strains of S. aureus , S. pneumoniae , E. faecalis , Cutibacterium acnes and C. difficile , less active against S. pyogenes and S. agalactiae , weakly active against Mycobacterium smegmatis and barely active against Mtb [ 122 ]. While cannabidiol ( 18 ) was inactive against E. coli , Klebsiella pneumoniae , Pseudomonas aeruginosa and Acinetobacter baumannii , it also displayed activity against four G-ve bacteria: N. gonorrhoeae , Neisseria meningitidis , M. catarrhalis and L. pneumophila [ 122 ]. It was also demonstrated that 18 was active against MSSA and MRSA biofilms, was active in topical in vivo models (though highly formulation-dependent) and that its MoA involved cytoplasmic membrane disruption [ 122 ]. It was recently shown that 18 could also act as an adjuvant with bacitracin, a cell wall inhibitor, via inhibition of undecaprenyl pyrophosphate dephosphorylation [ 123 ]. Genomic analysis demonstrated that less susceptible S. aureus strains contained mutations in the transporter farE / farR efflux pump system [ 123 ]. Additionally, screening of the Nebraska Transposon Mutant Library identified that strains with insertions involved in menaquinone biosynthesis had increased susceptibility to 18 that could be reversed by the addition of menaquinone [ 123 ]. The menaquinone biosynthesis pathway has been shown to be a promising drug target for S. aureus [ 124 , 125 ].

TNP-2092 ( 19 ) (CBR 2092; IV) is being developed by TenNor Therapeutics (Suzhou, People’s Republic of China) and completed a phase-II trial (NCT03964493) for the treatment of G+ve ABSSSI infections using IV dosing in September 2020. TenNor have also evaluated capsule administration of 19 for hyperammonemia/hepatic encephalopathy in a phase-II trial with patients with liver cirrhosis [ 126 , 127 ], while a phase-I trial (NCT04294862) for Prosthetic Joint Infection (PJI) employed IV administration [ 128 ]. TNP-2092 ( 19 ) is a rifamycin-quinolizinone (lead ABT-719) hybrid G+ve antibacterial discovered by Cumbre Pharmaceuticals [ 126 , 129 , 130 ] and its MoA is via inhibition of the targets of both antibacterial components: RNA polymerase (rifamycin) and DNA gyrase and topoisomerase IV (quinolone/quinolizinone) [ 131 ].

TNP-2198 ( 20 ) (IV) is another hybrid being developed by TenNor Therapeutics (Suzhou, People’s Republic of China); in this case, a rifamycin-metronidazole hybrid [ 132 ] for microaerophilic and anaerobic infections, which include gastrointestinal diseases associated with Helicobacter pylori , bacterial vaginosis and CDAD [ 133 ]. An H. pylori phase-II trial (CTR20220625 [ 134 ]) of capsules of 20 in combination with rabeprazole tablets (used to treat peptic ulcer disease) and amoxicillin capsules was completed in September 2022. An X-ray crystal structure was recently published that showed 20 bound to the rifamycin binding site on RNA polymerase with the nitroimidazole portion interacting directly with the DNA template-strand in the RNA polymerase active-center cleft, forming a hydrogen bond with a base of the DNA template strand [ 132 ]. This is supportive of RNA polymerase inhibition being involved in the MoA of 20 .

Afabicin ( 21 ) (Debio 1450, AFN 1720) [ 135 , 136 , 137 ] is a phosphate prodrug of afabicin desphosphono ( 22 ) (Debio 1452, AFN-1252; IV/po) being developed by Debiopharm Group (Lausanne, Switzerland). The lead compound was originally discovered by GSK (London, UK) and licensed to Affinium Pharmaceuticals, who were acquired by Debiopharm in February 2014. Afabicin ( 21 ) is being evaluated in a phase-II trial (NCT03723551) using an IV/oral switch strategy for the treatment of S. aureus bone or joint infections [ 138 ]. In an earlier phase-II trial (NCT02426918), 21 was shown to be clinically non-inferior to vancomycin/linezolid against staphylococcal ABSSSI [ 139 ]. Afabicin ( 21 ) specifically inhibits staphylococcal FabI [ 140 , 141 , 142 ], which is an essential enzyme in the final step of the fatty acid elongation cycle [ 143 ].

Peceleganan ( 23 ) (PL-5, V 681 ; topical) is a 26-mer α-helical cationic hybrid peptide of cecropin A and melittin B [ 144 , 145 ] being developed by Jiangsu ProteLight Pharmaceutical and Biotechnology (Jiangyin, People’s Republic of China). Peceleganan ( 23 ) is administered by spray and has successfully completed a phase-II trial in China (ChiCTR2000033334) for the treatment of bacterial wound infections [ 146 ]. No levels of 23 were detected in the patients’ blood. This indicated that there was minimal or no systemic exposure [ 146 ], a significant consideration since some cationic peptides have a history of causing nephrotoxicity. Peceleganan ( 23 ) has activity against both G+ve and G-ve bacteria [ 144 , 145 ] and there are plans to start a phase-III trial in 2023.

Recce-327 (R327; topical and IV) is an acrolein polymer with a molecular weight range of 1–1.5 kDa [ 147 ] being evaluated by Recce Pharmaceuticals (Perth, Australia) in a phase-I/II (ACTRN12621000412831) for the treatment of G+ve and G-ve burn wound infections. A phase-I trial (ACTRN12621001313820) using IV administration of Reece-327 is being conducted with the goal of developing the polymer for serious bacterial infections such as sepsis in the future. It has been reported that the polymer disrupts bacterial cellular bioenergetics via membrane potential and/or ATP synthesis [ 148 ].

Pravibismane ( 24 ) (MBN-101, bismuth ethanedithiol, BisEDT; topical) is a broad spectrum antibacterial with anti-biofilm activity [ 149 ] that is being developed by Microbion Corporation (Bozeman, MT, USA). A phase-II trial (NCT05174806) evaluating 24 as a topical treatment for diabetic foot infections started in June 2022, while a phase-II trial (NCT02436876) using intraoperative administration in patients diagnosed with an orthopedic infection was completed in July 2018. This clinical work is supported by the Cystic Fibrosis Foundation (Bethesda, MD, USA) and CARB-X (Boston, MA, USA). It has been reported that 24 can cause bacterial membrane depolarization, which disrupts cellular bioenergetics [ 150 ]. Bismuth has intrinsic antibacterial activity and is a component of Pepto Bismol ® (bismuth subsalicylate) [ 151 ] and Xeroform ® (bismuth tribromophenate) [ 152 ], and is used in combination with antibiotics and a proton pump inhibitor to treat H. pylori infections [ 153 ]. There has recently been a resurgence in interest in the antibacterial activity of metal complexes [ 154 , 155 ].

DNV-3837 ( 25 ) (MCB-3837; IV) is a phosphate prodrug of the oxazolidinone-quinolone hybrid DNV-3681 ( 26 ) (MCB-3681) being developed by Deinove (Montpellier, France). It is currently being evaluated in a phase-II CDI trial (NCT03988855) with IV administration [ 156 ]. Unfortunately, Deinove entered receivership proceedings in November 2022 [ 157 ]. The IV administration contrasts with most other antibacterials being developed for CDI, including non-traditionals [ 17 , 21 ], that are almost exclusively delivered orally with little or no systemic distribution (po topical). DNV-3837 ( 25 ) also showed G+ve activity against MRSA, Francisella tularensis and B. anthracis [ 158 , 159 , 160 ].

Ibezapolstat ( 27 ) (ACX-362E; po topical) is a bis-substituted guanine derivative that is a bacterial DNA polymerase IIIC inhibitor [ 161 , 162 , 163 , 164 ] that is being evaluated in a phase-II CDI trial (NCT04247542) [ 165 ] by Acurx Pharmaceuticals (White Plains, NY, USA). DNA polymerase IIIC is a new target for clinical development and is an essential enzyme in bacteria with low guanine and cytosine content, such as Bacillus , Clostridioides , Enterococcus , Mycoplasma , Lactobacillus , Listeria , Pneumococcus , Staphylococcus and Streptococcus [ 163 ].

CRS3123 ( 28 ) (REP3123; po topical) is a methionyl tRNA synthetase (MetRS) inhibitor (new diaryldiamine class) being developed by Crestone (Boulder, CO, USA) that selectively acts on S. aureus and C. difficile MetRS with little effect on G-ve and mammalian orthologs [ 166 , 167 ]. CRS3123 ( 28 ) prevents C. difficile sporulation, which leads to the inhibition of toxin production, and spares most normal gut flora [ 168 ]. CRS3123 ( 28 ) has completed two phase-I trials (NCT02106338 and NCT01551004) [ 169 , 170 ] and is currently being evaluated in a CDI phase-II trial (NCT04781387) versus a vancomycin comparator. In the previous pipeline review [ 23 ], 28 was listed as having its development halted or discontinued. This a reminder that relatively long delays can occur in antibacterial drug development, which have been exacerbated by the COVID-19 pandemic due to disruptions to clinical trial enrollments and day-to-day operations of many organizations [ 171 ].

Anti-mycobacterial compounds in phase-II trials (Table  4 , Fig.  6 )

Delpazolid ( 29 ) (RMX2001, LCB01-0371; po) is an oxazolidinone developed by LegoChem Biosciences, Inc. (Daejeon, Republic of Korea), which has activity against G+ve bacteria [ 172 ], Mtb [ 173 , 174 ] and NTMs [ 175 , 176 ]. Delpazolid ( 29 ) is currently being evaluated in a phase-II TB trial (NCT04550832) in combination with standard-dose bedaquiline, delamanid and moxifloxacin, compared to standard-dose bedaquiline, delamanid and moxifloxacin alone. In addition, a combination of 25 and vancomycin is being evaluated against vancomycin alone for hospitalized adults with MRSA bacteremia in a phase-IIa trial (NCT05225558). An early bactericidal activity (EBA) [ 177 ] phase-II trial (NCT02836483) showed that 29 monotherapy reduced the log-CFU of Mtb in sputum by approximately 25%, and had fewer side effects than other oxazolidinones [ 178 ].

Sutezolid ( 30 ) (PF-2341272, PNU-100480; po) [ 179 ] is an oxazolidinone originally developed by Upjohn & Co (later was incorporated into Pfizer (New York, NY, USA)) with activity against TB [ 174 , 180 , 181 , 182 ] and NTMs [ 176 ]. Sequella (Rockville, MD, USA) licensed 30 from Pfizer and completed a phase-II trial (NCT01225640) in December 2011 in naive patients with drug-sensitive pulmonary TB [ 183 ]. The European and Developing Countries Clinical Trials Partnership (EDCTP; The Hague, Netherlands) is leading a phase-II trial (NCT03959566) in partnership with Sequella evaluating a combination of 30 with bedaquiline, delamanid and moxifloxacin, compared against bedaquiline, delamanid and moxifloxacin alone. The TB Alliance (New York, NY, USA) and partners [ 184 ] will also evaluate sutezolid ( 30 ) in a phase-II (NCT05807399) and in combination with bedaquiline and pretomanid in a phase-II/III trial (NCT05686356) later in 2023.

Telacebec ( 31 ) (Q203; po) is an imidazo[1,2- a ]pyridine amide [ 185 , 186 , 187 ] being developed by Qurient Co., Ltd. (Seongnam-si, Republic of Korea) that completed an EBA TB phase-II trial (NCT03563599) in September 2019 [ 188 , 189 ]. The imidazo[1,2- a ]pyridine amide pharmacophore was identified during phenotypic high-content assays in infected macrophages and 31 inhibits TB growth via targeting QcrB, which is a subunit of the menaquinol cytochrome c oxidoreductase ( bc 1 complex) [ 185 , 190 , 191 ]. Telacebec ( 31 ) also has promise as a treatment for Buruli ulcer ( Mycobacterium ulcerans ) [ 192 , 193 ].

Fobrepodacin ( 32 ) (SPR720, pVXc-486; po) is a DNA gyrase inhibitor phosphate prodrug being investigated by Spero Therapeutics (Cambridge, MA, USA) in a phase-II trial (NCT05496374) with patients with MAC pulmonary disease. The active metabolite SPR719 ( 33 ) has activity against various Mycobacteria [ 194 , 195 , 196 ] and results from a phase-I trial (NCT03796910) suggested that predicted therapeutic exposures could be attained with once-daily oral administration [ 197 ]. Fobrepodacin ( 32 ) and SPR719 ( 33 ) were originally discovered by Vertex Pharmaceuticals (Boston, MA, USA) [ 198 , 199 , 200 ] and inhibit DNA synthesis via bacterial gyrase (GyrB) and topoisomerase IV ParE, which is a similar MoA to novobiocin [ 201 ].

BTZ-043 ( 34 ) (po) is the first member of a new benzothiazinone (BTZ) class of TB antibacterials that completed a phase-I/II trial (NCT04044001) in May 2022. This study evaluated the safety, tolerability and EBA of 34 , and was led by the EDCTP (The Hague, Netherlands). BTZ-043 ( 34 ) inhibits the essential mycobacterial cell wall biosynthesis enzyme decaprenylphosphoryl‐β‐D‐ribose (DPR) 2′‐oxidase (DprE1) via in vivo reduction of the nitro group, generating a reactive nitroso intermediate that forms a covalent semi-mercaptal adduct with cysteine-387 [ 202 , 203 , 204 , 205 , 206 ]. It has been shown that BTZs can be de-aromatized in vivo through the formation of a Meisenheimer complex, which could also reduce their in vivo half-lives [ 207 , 208 ]. A BTZ analog, macozinone ( 53 , Fig.  9 ) is being evaluated in a phase-I trial.

Quabodepistat ( 35 ) (OPC-167832; po) is an antitubercular 3,4-dihydrocarbostyril derivative [ 209 ] being developed by Otsuka Pharmaceutical (Tokyo, Japan) that started a phase-II trial (NCT05221502) in April 2022 in combination with delamanid and bedaquiline, compared to a combination of rifampin, isoniazid, ethambutol, and pyrazinamide. Quabodepistat ( 35 ), which completed a phase-I/II trial in February 2022 (NCT03678688), exerts its anti-mycobacterial activity through inhibition of the cell wall synthesis enzyme DprE1 [ 210 ], which is the same target as BTZ-043 ( 34 ), macozinone ( 53 ) and TBA-7371 ( 38 ).

GSK3036656 ( 36 ) (GSK656; po) is a boron containing leucyl t-RNA synthetase inhibitor (new MoA) [ 211 , 212 ] that GSK (London, UK) are currently investigating in a phase-II trial (NCT05382312) in combination with either delamanid, bedaquiline, both delamanid and bedaquiline or standard of care for 14 days in participants with newly diagnosed sputum smear positive drug-sensitive pulmonary TB. A phase-II EBA TB trial (NCT03557281) for 36 was completed in December 2021. A dechloro analog, epetraborole ( 13 , Fig.  4 ), is currently in a phase-II/III trial (NCT05327803) against treatment-refractory MAC lung disease.

TBA-7371 ( 37 ) (po) is a substituted 1,4-azaindole that is being developed as a new TB treatment by the Global Alliance for TB Drug Development (New York, NY, USA), the Foundation for Neglected Disease Research (Bangalore, Republic of India) and the Bill & Melinda Gates Medical Research Institute (Cambridge, MA, USA). TBA-7371 ( 37 ) is currently being evaluated in a phase-II EBA and pharmacokinetic (PK) trial (NCT04176250) in patients with rifampicin-sensitive TB. TBA-7371 ( 37 ) is a non-covalent DprE1 inhibitor discovered by scaffold hopping from telacebec ( 31 ), which has a different mechanism [ 213 , 214 , 215 ].

Sudapyridine ( 38 ) (WX-081; po) is a bedaquiline analog with a chlorophenyl-methoxypyridyl group replacing the bedaquiline bromo-2-methoxy-3-quinolyl substituent [ 216 ] being developed by Shanghai Jiatan Biotech (Shanghai, People’s Republic of China). Sudapyridine ( 38 ) is being evaluated in a phase-II EBA trial (NCT04608955) in patients with susceptible and drug-resistant TB. Sudapyridine ( 38 ) has a similar in vitro and in vivo activity profile to bedaquiline, but had no adverse effects on blood pressure, heart rate, or qualitative ECG parameters during non-clinical toxicology studies [ 217 ]. Sudapyridine ( 38 ) also has in vitro activity against most NTM species [ 218 ].

Pyrifazimine ( 39 ) (TBI-166; po) is a clofazimine analog [ 219 ] (riminophenazine class) that completed a phase-II EBA TB trial (NCT04670120) in June 2021 run by the Institute of Materia Medica (Shanghai, People’s Republic of China), Chinese Academy of Medical Sciences (Beijing, People’s Republic of China) and Peking Union Medical College (Beijing, People’s Republic of China). Although clofazimine has been used to treat leprosy ( Mycobacterium leprae infections) since 1962 and was recently incorporated into some short-course MDR-TB regimens [ 220 , 221 ], its tissue accumulation can cause skin discoloration that can take months to clear. Pyrifazimine ( 39 ) was designed to maintain activity against TB, have improved PK/pharmacodynamics (PD) properties, and cause less skin discoloration [ 222 , 223 , 224 , 225 ].

Non-traditional antibacterial compounds in phase-II trials (Table  4 , Fig.  7 )

Fluorothiazinon ( 40 ) (ftortiazinon, fluorothyazinon, C-55; po) is an orally administered inhibitor of the bacterial type III secretion system (T3SS), which is a highly conserved G-ve anti-virulence target [ 226 ] Fluorothiazinon ( 40 ) was developed by the Gamaleya Research Institute of Epidemiology and Microbiology (Moscow, Russia) [ 227 , 228 , 229 , 230 ], and has been evaluated in a phase-II trial (NCT03638830) in combination with the cephalosporin cefepime ( 41 ) as a potential treatment for patients with cUTI caused by P. aeruginosa .

Dovramilast ( 42 ) (CC-11050, AMG-634; po) is an isoindole phosphodiesterase type 4 (PDE4) inhibitor being developed for TB [ 231 , 232 ] and leprosy type 2 reactions by Medicines Development for Global Health (Melbourne, Australia), which licensed 42 from Amgen (Thousand Oaks, CA, USA) in December 2020 [ 233 , 234 ]. Dovramilast ( 42 ) is being evaluated in a phase-II trial (NCT03807362) at The Leprosy Mission Nepal (Katmandu, Nepal) for patients with erythema nodosum leprosum (ENL), which is an inflammatory disorder triggered by leprosy. Another phase-II trial (NCT02968927) run by The Aurum Institute NPC (Johannesburg, South Africa) has been completed [ 235 , 236 ]. PDE4 inhibitors are an adjunctive host-directed therapy designed to modulate the inflammatory response to Mtb infection by reducing, but not fully blocking, TNF-α production by the host cells. The NCT02968927 trial used 42 in combination with 2HRZE/4HR therapy, which is 2 months of isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E), followed by a continuation phase of 4 months of isoniazid and rifampicin, while the NCT03807362 trial examines the safety and efficacy of CC-11050 as a monotherapy.

Traditional antibacterial compounds in phase-I trials (Table  5 , Figs.  8 and 9 )

SPR206 ( 43 ) (IV) is a polymyxin analog being developed by Spero Therapeutics (Cambridge, MA, USA) with activity against MDR G-ve bacteria [ 237 ] and reduced nephrotoxicity compared to polymyxin. SPR206 ( 43 ) has completed three phase-I trials (NCT03792308, NCT04868292, and NCT04865393), with a phase-II trial planned for Q4 2023 [ 238 ]. Everest Medicines (Shanghai, People’s Republic of China) had licensed the rights for 43 in China, South Korea and several Southeast Asian countries [ 239 ], while Pfizer (New York, NY, USA) has the remaining rights outside of the USA [ 238 ].

MRX-8 (IV) is another polymyxin analog being developed by MicuRx (Hayward, CA, USA and Shanghai, People’s Republic of China) against G-ve bacteria [ 240 , 241 , 242 ] that completed a phase-I trial in 2021 (NCT04649541), while another phase-I is ongoing in China [ 243 ]. Although MRX-8’s structure has not been publicly disclosed, it is a polymyxin B analog with a fatty acid tail linked via a polar ester group to form a ‘soft’ prodrug [ 241 , 244 ].

QPX-9003 ( 44 ) (F365, BRII-693; IV) is also a polymyxin derivative being developed by Qpex Biopharma (San Diego, CA, USA). It is a potential treatment for P. aeruginosa and A. baumannii infections and completed a phase-I trial in July 2022 (NCT04808414) [ 245 ]. QPX-9003 ( 44 ) was reported by researchers at Monash University (Melbourne, Australia) and Qpex to have reduced nephrotoxicity, acute toxicity and in vitro lung surfactant inactivation compared to other polymyxins [ 246 ]. Brii Biosciences (Durham, NC, USA and Shanghai, People’s Republic of China) have licensed QPX-9003 ( 44 ) for development in the Greater China region [ 101 ].

RG6319 (administration route not disclosed) is an inhibitor of LepB, which is an E. coli Type I signal peptidase (SPase), listed on Roche’s (Basel, Switzerland) pipeline as being evaluated in a phase-I clinical trial for cUTI [ 247 ]. SPases are enzymes that hydrolyze N -terminal signal peptides from proteins that are secreted across the cytoplasmic membrane and have a critical role in the viability and virulence of bacteria [ 248 ]. Although the structure of RG6319 has not been disclosed, Genetech (San Francisco, CA, USA) and The Scripps Research Institute (La Jolla, CA, USA) have been evaluating derivatives of the arylomycins, which are Streptomyces -derived SPase inhibitors, such as G0775 [ 249 , 250 ].

Zifanocycline ( 45 ) (KBP-7072; IV/po) is a tetracycline derivative (aminomethylcycline) being developed by KBP BioSciences (Princeton, NJ, USA) that has completed three phase-I trials (NCT02454361, NCT02654626, and NCT04532957) and is currently being evaluated in another phase-I trial (NCT05507463). Zifanocycline ( 45 ) has broad spectrum antibacterial activity [ 251 , 252 , 253 ] and a preprint has disclosed an X-ray structure of 45 bound to the Thermus thermophilus 30 S ribosomal subunit [ 254 ]. As with CRS3123 ( 28 ), zifanocycline ( 45 ) was listed as discontinued or halted in the previous review [ 23 ].

Apramycin ( 46 ) (EBL-1003; IV) is an aminoglycoside being developed by Juvabis AG (Zurich, Switzerland) that completed a phase-I trial (NCT04105205) in October 2020. A new phase-I trial (NCT05590728) was recently started by the National Institute of Allergy and Infectious Diseases (NIAID; Rockville, MD, USA). Apramycin ( 46 ) has activity against carbapenem- and aminoglycoside-resistant Enterobacteriaceae, A . baumannii and P. aeruginosa [ 255 , 256 ]. Apramycin ( 46 ) has been widely used as a veterinary antibiotic to treat E. coli and other G-ve infections [ 257 ], with European approval to treat colibacillosis and salmonellosis in calves, bacterial enteritis in pigs, colibacillosis in lambs and E. coli septicemia in poultry [ 258 ]. It was discovered in the 1960s at Eli Lilly & Co (Indianapolis, IN, USA) as a NP produced by Streptomyces tenebrarius [ 259 , 260 ].

PLG0206 ( 47 ) (WLBU2; topical and IV) is a 24 residue membrane disrupting cationic peptide [ 261 , 262 ] being evaluated by Peptilogics (Pittsburgh, PA, USA) in a phase-I trial (NCT05137314) for its potential to treat PJI in conjunction with the DAIR (debridement, antibiotics, and implant retention) surgical procedure after total knee arthroplasty. PLG0206 ( 47 ) has also successfully completed a phase-I trial with IV administration [ 263 ]. PLG0206 ( 47 ) has broad spectrum activity against G+ve and G-ve bacteria, including biofilms [ 261 , 264 , 265 ].

PL-18 ( 48 ) (HPRP-A1; topical) is a 15-mer α-helical cationic peptide derived from the N -terminus of the H. pylori ribosomal protein L1 (RpL1) that is being developed by Jiangsu ProteLight Pharmaceutical and Biotechnology (Jiangyin, People’s Republic of China). In August 2022, 48 started a phase-I trial (NCT05340790) in Australia for bacterial vaginosis using suppository administration. PL-18 ( 48 ) has activity against G-ve and G+ve bacteria [ 144 , 145 , 266 , 267 ] and fungi [ 266 ], as well as induction of HeLa cell apoptosis [ 268 ] and hemolytic activity [ 266 , 267 ]. These off-target activities suggest why topical administration is required for 48 .

Murepavadin ( 49 ) (POL7080, RG7929; inhalation) is a synthetic 14-mer cyclic peptide derived from protegrin I being developed by Spexis (Basel, Switzerland), which was formed through a merger of EnBiotix and Polyphor in December 2021. Murepavadin ( 49 ) has potent and selective activity against P. aeruginosa via binding to the N -terminal of the β-barrel protein LptD (Imp/OstA), a novel MoA [ 269 , 270 , 271 ]. Murepavadin ( 49 ) is reported to be in a phase-I trial for cystic fibrosis using inhaled administration [ 272 ], and was previously investigated in two phase-III trials for the treatment of Pseudomonas nosocomial pneumonia (NCT03582007) and VAP infections (NCT03409679). However, these trials were halted due to adverse events — an increase in serum creatinine and acute kidney injury in the nosocomial pneumonia trial in 2019 [ 273 ].

TXA709 ( 50 ) (po) is an anti-MRSA prodrug of TXA707 ( 51 ) that has been evaluated in a phase-I trial conducted by TAXIS Pharmaceuticals (Monmouth Junction, NJ, USA) [ 274 ]. TXA707 ( 50 ) is an inhibitor of the new antibacterial target FtsZ, which is the bacterial homolog of tubulin that plays a critical role in bacterial cell wall division in both G+ve and G-ve bacteria [ 275 , 276 ]. Prolysis Ltd (Oxford, UK) originally identified PC190723 [ 277 , 278 , 279 ] and replacement of its Cl substituent with a CF 3 group in TXA707 ( 51 ) enhanced metabolic stability, PK properties and in vivo efficacy against S. aureus [ 280 , 281 ].

RG6006 (RO7223280, Abx MCP; IV) is being developed by Roche (Basel, Switzerland) and a phase-I trial (NCT05614895) was started in December 2022 in critically ill participants with bacterial infections using IV administration. RG6006 will be developed as a treatment for A. baumannii infections [ 247 ] and is a tethered macrocyclic peptide [ 282 , 283 ]; however, the structure and MoA have not been publicly disclosed.

BWC0977 ( 52 ) (IV/po) is an oxazolidinone containing ‘novel bacterial topoisomerase inhibitor’ (NBTI) [ 284 ] with similar activity against DNA gyrase GyrA and topoisomerase IV [ 284 , 285 , 286 ] being developed by Bugworks Research Inc (Bangalore, Republic of India). BWC 0977 ( 52 ) is being evaluated in a phase-1 trial (NCT05088421) using IV administration for treating critical care G-ve infections [ 287 , 288 ] with later oral step-down administration.

Anti-mycobacterial compounds in phase-I trials (Table  5 , Fig.  9 )

Macozinone ( 53 ) (PBTZ169; po) is a benzothiazinone (BTZ) derivative [ 289 ] that was evaluated in a phase-II EBA TB trial (NCT03334734) by Nearmedic Plus LLC (Moscow, Russia), but the trial was discontinued in February 2018 due to slow enrollment. The Innovative Medicines for Tuberculosis (iM4TB) Foundation (Lausanne, Switzerland) is leading the development of 53 in the rest of the world and completed a Phase-I trial (NCT03776500) in March 2020. Macozinone ( 53 ) is a second generation analog of BTZ043 ( 34 , Fig.  6 ) with the same MoA (inhibition of the mycobacterial cell wall biosynthesis enzyme DprE1) with superior physicochemical properties [ 289 ]; however, efforts have been undertaken to improve its PK and PD properties [ 290 ].

TBI-223 ( 54 ) (po) is an oxazolidinone [ 291 ] being developed by the TB Alliance (New York, NY, USA) and the Institute of Materia Medica (Shanghai, People’s Republic of China) that has completed two phase-I trials (NCT03758612 and NCT04865536). TBI-223 ( 54 ) was recently found to be active against S. aureus in MRSA mouse models [ 292 ].

TBAJ-876 ( 55 ) (po) is a bedaquiline analog (diarylquinolines class) with activity against Mtb [ 293 ] and M. abscessus [ 294 ], and minimal hERG channel inhibition [ 295 , 296 ] that was discovered at the University of Auckland (Auckland, New Zealand). TBAJ-876 ( 55 ) is now being developed by the TB Alliance (New York, NY, USA) and completed a phase-I trial (NCT04493671) in November 2022, which focused on safety, tolerability, and PK. In September 2022, another phase-I trial (NCT05526911) was initiated that also evaluates its effects on CYP3A4 and P-glycoprotein. Like bedaquiline, 55 is an inhibitor of mycobacterial F-ATP synthase [ 297 ] but does not retain bedaquiline’s protonophore activity [ 298 ]. Cryogenic electron microscopy (cryo-EM) was recently used to show the binding of 55 to the F o domain in M. smegmatis F 1 F o -ATP synthase [ 299 ].

TBAJ-587 ( 56 ) (po) is another bedaquiline analog [ 295 ] with variations in the substituents on one pyridyl ring that lead to more potent in vitro and in vivo activity against Mtb [ 300 ]. TBAJ-587 ( 56 ) is currently in a phase-1 trial (NCT04890535) to evaluate its safety, tolerability, and PK.

GSK2556286 ( 57 ) (GSK-286; po) is a substituted uracil derivative being evaluated by GSK (London, UK) in a phase-I trial (NCT04472897) as a potential TB treatment [ 301 ]. GSK2556286 ( 57 ) was discovered by screening against Mtb that resides within human (THP-1) macrophage-like differentiated monocytes and had an IC 50 of 0.07 µM [ 302 ]. In addition, 57 required cholesterol to show activity in an axenic culture and resistance mutations were mapped to Mtb adenylyl cyclase (cya) Rv1625c [ 302 , 303 , 304 ], which has been implicated in cholesterol utilization [ 305 ]. This is a new MoA.

Non-traditional antibacterial compounds in phase-I trials (Table  5 , Fig.  10 )

BVL-GSK098 ( 58 ) [ 306 ] (po) is the first member of a new non-traditional, anti-TB antibacterial class (spiroisoxazoline) being developed by BioVersys (Basel, Switzerland) and GSK (London, UK). BVL-GSK098 ( 58 ) completed a phase-I trial (NCT04654143) in May 2022. BVL-GSK098 works through inactivation of a Mtb TetR-like repressor, EthR2, which reverses ethionamide ( 59 )-acquired resistance and increased basal sensitivity to 59 [ 307 , 308 ]. A phase-II EBA trial (NCT05473195) is scheduled to evaluate ethionamide ( 59 ) with or without BVL-GSK098 ( 58 ) in participants with rifampicin- and isoniazid-susceptible pulmonary TB.

GSK3882347 (po) is an E coli Type 1 fimbrin D-mannose specific adhesin (FimH) inhibitor being evaluated by GSK (London, UK) and Fimbrion Therapeutics (St. Louis, MO, USA) with support from CARB-X (Boston, MA, USA) [ 309 ]. GSK3882347 completed a phase-I trial (NCT04488770) in May 2021 and is currently being evaluated in a Phase-Ib trial (NCT05138822) in participants with acute uUTI. A majority of UTIs are caused by uropathogenic E. coli (UPEC) [ 310 ], which use their type 1 pili to adhere to the cell wall via FimH adhesin [ 311 ]. Targeting the mannose-binding lectin domain of FimH prevents UPEC from binding to the bladder wall and is a promising antivirulence approach for UTI and Crohn’s Disease [ 312 , 313 , 314 ]. Although the structure of GSK3882347 has not been publicly disclosed, it is likely to be a mannose-derived biphenyl derivative [ 315 ].

ALS4 (po) is an S. aureus anti-virulence antibacterial being developed by Aptorum Therapeutics Limited (Hong Kong, People’s Republic of China) that has completed one phase-II trial (NCT05274802). Staphyloxanthin is a golden colored carotenoid with antioxidant activity that helps to neutralize reactive oxygen species (ROS) secreted by neutrophils, which protects bacteria [ 316 , 317 ]. ALS4 is an inhibitor of 4,4ʹ-diapophytoene desaturase (CrtN), which is an enzyme involved in the biosynthesis of staphyloxanthin; however, although the structure of ALS4 has not been publicly disclosed, it is likely to be related to NP16 [ 318 , 319 ].

β-Lactam/β-lactamase Inhibitor (BL/BLI) Combinations Undergoing Clinical Evaluation

The discovery of the Streptomyces -derived BLI clavulanic acid was a significant breakthrough that rescued the use of many BL antibiotics by inactivating enzymes responsible for their destruction. There have been four new BL/BLI combinations approved since 2014 (Table  1 ): Zerbaxa in 2014 (contains a new cephalosporin, ceftolozane), Avycaz in 2015 (contains a new DBO-type BLI, avibactam), Vabomere in 2017 (contains a new boronate-type BLI, vaborbactam), and Recarbrio in 2019 (contains a new DBO-type BLI, relebactam), but no new combinations were approved from 2019–2022. In this section, ten new BL/BLI combinations are currently being evaluated in clinical trials or under an NDA/MAA filing are discussed (Table  6 , Figs.  11 – 13 ). It should be noted that BL/BLI combinations usually move straight from phase-I into phase-III trials.

BL/BLI combinations in NDA/MAA filing (Table  6 , Fig.  11 )

Durlobactam ( 60 ) (ETX2514) + sulbactam ( 61 ) (combination: SUL-DUR, ETX2514SUL; IV) is being developed by Entasis Therapeutics (a subsidiary of Innoviva, Burlingame, CA, USA) and completed a phase-III trial (NCT03894046) for treatment of infections caused by A. baumannii-calcoaceticus (ABC) complex [ 320 , 321 , 322 ] in June 2021. In this trial, SUL-DUR demonstrated statistical non-inferiority versus colistin for the primary end point of 28-day all-cause mortality in patients with carbapenem-resistant ABC infections and a significant difference in clinical cure rates, as well as a statistically significant reduction in nephrotoxicity [ 323 ]. On 17 April 2023, the US FDA Antimicrobial Drugs Advisory Committee voted 12-0 in favor of SUL-DUR for the treatment of adults with HABP/VABP caused by susceptible ABC strains. Footnote 2 Durlobactam ( 60 ) is a DBO-type BLI [ 324 , 325 , 326 ], while sulbactam ( 61 ) is a clavulanic acid-type BLI first launched in 1986 that also has direct-acting antibacterial activity against Acinetobacter spp., but requires co-administration of another BLI to restore its activity against MDR strains.

BL/BLI combinations in phase-III trials (Table  6 , Fig.  12 )

Taniborbactam ( 62 ) (VNRX-5133; IV) [ 327 ] + cefepime ( 41 ) is being developed by VenatoRx Pharmaceuticals (Malvern, PA, USA) and completed a phase-III trial (NCT03840148) in December 2021 for cUTI, including acute pyelonephritis. VenatoRx have revealed that cefepime-taniborbactam had a superior primary efficacy endpoint to the carbapenem meropenem ( 66 ) in this trial with a similar safety profile [ 328 ], and plan to submit an NDA to the US FDA in 2023 [ 329 ]. The taniborbactam ( 62 ) + cefepime ( 41 ) combination has activity against E. coli , K pneumoniae , carbapenemase-producing Enterobacterales and P. aeruginosa [ 330 , 331 , 332 ]. Taniborbactam ( 62 ) is a bicyclic boronate BLI [ 333 ] (new class) that is effective against both serine- and metallo-β-lactamases, including extended-spectrum β-lactamase (ESBL), OXA, KPC, NDM and VIM enzymes, but not IMP [ 327 , 334 ], while cefepime ( 41 ) is a fourth-generation cephalosporin first approved in 1994.

Enmetazobactam ( 63 ) (AAI 101; IV) is a clavulanic acid-type BLI with a structure closely related to tazobactam with a methyl substituent on the tazobactam triazole ring. It has activity against ESBLs and some class A and D carbapenemases [ 335 , 336 , 337 ], and is being developed by Allecra Therapeutics (Weil am Rhein, Germany and Saint Louis, France). A combination of 63 and the cephalosporin cefepime ( 41 ) completed a phase-III trial (NCT03687255) in February 2020 for cUTI using IV administration, and successfully met criteria for non-inferiority, as well as superiority to piperacillin-tazobactam with respect to the primary efficacy outcome of clinical cure and microbiological eradication [ 338 ]. Allecra Therapeutics is planning to submit an MAA in Europe, followed by an NDA in the USA.

Zidebactam ( 64 ) (WCK 5107; IV) is a DBO-type BLI being developed by Wockhardt Limited (Mumbai, Republic of India) that inhibits PBPs and several β-lactamases, while enhancing BL activity [ 339 ] against A. baumannii , P. aeruginosa and CRE [ 340 , 341 , 342 ]. A combination of 63 and cefepime ( 41 ) (combination WCK 5222, FEP-ZID) started a phase-III trial (NCT04979806) in August 2022 as an IV administered treatment for cUTI and acute pyelonephritis. A phase-I trial (NCT05645757) of 63 in combination with the carbapenem ertapenem (combination WCK 6777) should commence soon, with this combination showing potent in vitro activity against many carbapenemases and β-lactamases [ 343 ].

BL/BLI combinations in phase-I trials (Table  6 , Fig.  13 )

Nacubactam ( 65 ) (OP0595, FPI-1459, RG6080, RO7079901; IV) is a DBO-type BLI [ 344 , 345 , 346 ], which was developed by Meiji Seika Pharma (Tokyo, Japan). Meiji Seika and Fedora Pharmaceuticals (Edmonton, AB, Canada) had previously partnered with Roche (Basel, Switzerland) [ 347 , 348 ] and several phase-I trials have been completed (Meiji Seika: NCT02134834; Roche: NCT02975388, NCT03182504), as well as two phase-I trials in combination with meropenem ( 66 ) (Roche: NCT02972255, NCT03174795). Nacubactam ( 65 ) is still listed as OP0595 on Meiji Seika’s latest pipeline [ 349 ], while Fedora’s website indicates that the combination is available for licensing [ 350 ].

Xeruborbactam ( 67 ) (QPX7728; IV) is a bicyclic boronate BLI [ 333 ] (new class) being developed by Qpex Biopharma (San Diego, CA, USA) that displays broad spectrum β-lactamase inhibition, including against class B and class D enzymes [ 351 , 352 , 353 ], as well as some intrinsic G-ve antibacterial activity [ 354 ]. An IV administered combination of 67 and an undisclosed BL (QPX2014) has completed two phase-I trials (NCT04380207 and NCT05072444) with an aim to treat serious drug resistant Acinetobacter , Pseudomonas and Enterobacterales infections. An orally administered xeruborbactam prodrug, QPX7831 ( 68 ) [ 355 ] (po), completed a phase-I trial (NCT04578873) in August 2022 and there are plans to use 68 in combination with an undisclosed oral BL (QPX2015) to treat ESBLs and carbapenem-resistant Enterobacterales (CRE) infections.

A combination of the DBO-type BLI ETX0282 ( 69 ) (po) and the cephalosporin cefpodoxime proxetil ( 70 ), collectively called ETX0282CPDP, was evaluated in a phase-I trial that finished in September 2019 (NCT03491748) by Entasis Therapeutics (Waltham, MA, USA), who are now a wholly owned subsidiary of Innoviva (Burlingame, CA, USA). Both ETX0282 ( 69 ) and cefpodoxime proxetil ( 70 ) are esterase-cleavable prodrugs, of ETX1317 ( 71 ) and cefpodoxime ( 72 ) respectively, and the combination is being developed to treat multidrug resistant and CRE infections [ 356 , 357 ]. ETX1317 ( 71 ) has an ( R )-2-( N -oxy)-2-fluoroacetic acid unit in place of the N -oxy-sulfonic acid group present in other DBOs and displays some innate G-ve activity, in addition to BLI activity [ 356 , 357 ].

A ledaborbactam etzadroxil ( 73 ) (VNRX-7145) + ceftibuten ( 74 ) combination (po) [ 358 ] is being developed by VenatoRx Pharmaceuticals (Malvern, PA, USA). This combination is currently being evaluated in two phase-I trials (NCT05527834 and NCT05488678) and has previously completed two other phase-I trials (NCT04243863 and NCT04877379). Ledaborbactam etzadroxil ( 73 ) is an esterase-cleavable prodrug of the bicyclic boronate-type BLI (new class [ 333 ]) of ledaborbactam ( 75 ) (VNRX-5236) [ 358 ], while 74 is a third-generation cephalosporin first approved in 1995. The ledaborbactam etzadroxil ( 73 ) + ceftibuten ( 74 ) combination is active against clinically-derived Enterobacterales that express ESBLs and serine carbapenemases [ 359 , 360 , 361 ].

A ternary combination therapy combining funobactam ( 76 ) (XNW-4107) + imipenem ( 77 ) + cilastatin ( 78 ) (IV) is being developed by Suzhou Sinovent Pharmaceuticals (Sinovent) (Suzhou, People’s Republic of China). Funobactam ( 76 ) is a DBO-type BLI [ 362 ], while imipenem ( 77 ) is a carbapenem-type BL that was approved in combination with cilastatin ( 78 ) in 1985, as well as in combination with the DBO relebactam and 78 in 2019 [ 363 ]. Cilastin ( 78 ) is a renal dehydropeptidase inhibitor that reduces the rate of 77 metabolism. Funobactam ( 76 ) has completed two phase-I trials (NCT04482569, NCT04802863) and two phase-I trials are ongoing (NCT04801043, NCT04787562). Two phase-III trials have been announced that will evaluate the funobactam ( 76 ) + imipenem ( 77 ) + cilastatin ( 78 ) combination against cUTI (NCT05204368) and HABP/VABP (NCT05204563).

CTB + AVP (PF-07612577; po) is a combination of the cephalosporin ceftibuten ( 74 ) (PF-06264006) and the DBO-type BLI avibactam ( 80 ) prodrug, AVP ( 79 ) (PF-07338233, ARX-006, ARX-1796), under development by Pfizer (New York, NY, USA). CTB + AVP is being evaluated in a phase-I trial (NCT05554237), which started in October 2022. Avibactam ( 80 ) in combination with ceftazidime (Avycaz) was first approved in 2015 by the US FDA and is used to treat cIAI and cUTI [ 364 ]. AVP ( 79 ) was first developed by Arixa Pharmaceuticals (Palo Alto, CA, USA) [ 365 ], who were acquired by Pfizer in October 2020 [ 366 ], and a prior phase-I trial (NCT03931876) had already been completed.

Compounds discontinued from clinical development

Compounds and BL/BLI combinations that have been discontinued from clinical development or appear to have had their development halted since the 2019 review [ 25 ] are listed in Table  7 with notes indicating any known reasons for their failure or lack of progress.

Analysis of compounds undergoing clinical trials

Numbers of compounds undergoing clinical evaluation and their source derivation.

There were 62 antibacterial clinical candidates under clinical investigation (Figs.  14 and 15 ) on 31 December 2022 — ten BL/BLI inhibitor combinations and 52 small molecules, mammalian-derived peptides, and a direct acting polymer. Five of the 62 are non-traditional antibacterials that target virulence (fluorothyazinone ( 40 ), GSK3882347 and ALS4), resistance (BVL-GSK098 ( 58 )) and host inflammation (dovramilast ( 42 )) (Tables  4 and 5 , Figs.  7 and 10 ). Of the ten BL/BLI combinations, one is in NDA/MAA (Table  6 , Fig.  11 ), three are in phase-III (Table  6 , Fig.  12 ) and six are in phase-I (Table  6 , Fig.  13 ). Of the remaining 52 compounds, one is in NDA/MAA (Table  3 , Fig.  3 ), six are in phase-III (Table  3 , Fig.  4 ), 25 are in phase-II (Table  4 , Figs.  5 – 7 ) and 20 are in phase-I (Table  5 , Figs.  8 – 10 ). The source derivation of the 62 compounds was divided into 41 that were synthetically derived (S), 17 that were NP derived (NP), and four that were protein/mammalian peptide derived (P) (Fig.  14 ).

While there was a similar number of compounds in the different development phases in 2011, 2013 and 2015 analyses (except for a reduced number in phase-III trials in 2011 (6) compared to 2013 (16) and 2015 (15)), the number in phase-I trials increased to 22 in 2019 [ 23 ] from an average of 12 compounds in 2011-2015 [ 24 , 25 , 26 ], and this was even higher at 26 in 2022 (Fig.  15 ). The number of compounds in phase-II also increased (from 18 in 2019 to 25 in 2022), reflecting the successful progression of several of the 2019 phase-I candidates and the entry of new antibacterials. At least 18 of the 26 phase-I compounds target G-ve bacteria (11 traditional compounds, one anti-virulence and six BLI combinations), with four of these also possessing G+ve activity, while there are an additional eight with G+ve only activity (six against TB and two against MRSA). While the overall numbers are still low compared to other therapeutic disease indications, the clinical pipeline is now starting to resemble the more traditional progression of attrition, rather than the flat or inverse progressions seen in 2011 [ 26 ], 2013 [ 25 ] and 2015 [ 24 ], and this likely reflects the success of push incentives driving innovative antibiotic discovery [ 6 , 7 , 8 , 9 , 10 ].

New antibacterial pharmacophore analysis

A pharmacophore is the common subunit of active molecules that interact with biological targets. It is crucial to develop new antibacterial drugs with new MoA and/or pharmacophores to slow down drug resistance and to potentially allow the identification of new combination therapies. This is also why there is considerable excitement around the potential of non-traditional antibacterials, along with the yet-to-be-proven hypothesis that some modalities, such as antivirulence strategies, will not lead to resistance since bacterial survival is not directly targeted [ 17 , 18 , 20 , 21 ].

In this review, new pharmacophores not previously found in human antibacterial drugs have been analyzed as a measure of antibacterial structure innovation (Table  8 ). In Table  8 , compounds with new MoA not previously found in previously approved antibacterial drugs are underlined. The MoA of most traditional small molecule antibacterial drugs can be categorized into four major ‘macro’ level classes: cell wall, protein synthesis, DNA synthesis, and RNA synthesis inhibitors [ 367 ]. There are 34 different compounds — 15 in phase-I, 15 in phase-II and 4 in phase-III/NDA (Fig.  16 ) — and this total is significantly higher than identified in previous reviews: 11 in 2011 [ 26 ], 17 in 2013 [ 25 ], 15 in 2015 [ 24 ] and 19 in 2019 [ 23 ] (Fig.  17 ). Twenty-six of these compounds target the well-established ‘macro’ targets: cell wall (17), DNA (6) and protein synthesis inhibition (3). There are no novel RNA synthesis inhibitors in clinical development. Since the 2019 review [ 23 ], the boronate BLI class has expanded with the bicyclic boronates class, which includes taniborbactam ( 60 ), xeruborbactam ( 65 ) and ledaborbactam etzadroxil ( 71 ), now considered to be a new class [ 21 , 22 ].

Existing antibacterial classes that inhibit the bacterial cell envelope include the BL, glycopeptide, polymyxin, daptomycin (lipopeptide), fosfomycin, and cycloserine classes. The new cell envelope acting antibacterials inhibit several different targets (LptD: murepavadin ( 49 ), FabI: afabicin ( 21 ), 3 × DprE: BTZ-043 ( 34 ) and macozinone ( 53 ), quabodepistat ( 35 ) and TBA-7371 ( 37 ), and FtsZ: TXA709 ( 62 )) and six perturb bacterial membranes through less defined mechanisms (exeporfinium ( 17 ), cannabidiol ( 18 ), Recce-347, and the three cationic peptides, peceleganan ( 23 ), PLG0206 ( 47 ) and PL-18 ( 48 )) (Table  8 ). Although the structure of RG6319 has not been disclosed, it is likely to be an arylomycin derivative that inhibits E. coli Type 1 signal peptidase, which is a key enzyme in transporting enzymes across the cytoplasmic membrane to the outer cell wall [ 248 ].

The (fluoro)quinolone class are DNA synthesis inhibitors (DNA gyrase GyrA and topoisomerase IV parC [ 201 ]) that are routinely used in clinical practice, while novobiocin, which is a DNA gyrase GyrB and topoisomerase IV ParE inhibitor, was briefly used as an antibacterial over 50 years ago [ 201 , 368 ]. BWC0977 ( 52 ) belongs to a new antibacterial class and equally inhibits both DNA gyrase GyrA and topoisomerase IV. Fobrepodacin ( 32 ) is an ‘ethyl urea benzimidazole’ that also binds to both GyrB and ParE, gepotidacin ( 10 ) inhibits GyrA at a different binding site to the quinolones, and zoliflodacin ( 11 ) inhibits GyrB. Ibezapolstat ( 27 ) is the first member of the dichlorobenzyl guanine class that inhibits DNA polymerase IIIC, while MGB-BP-3 ( 16 ) is a DNA minor groove binder.

Bacterial protein synthesis inhibition can be caused by several compound classes including macrolides, aminoglycosides, tetracyclines, lincosamides, chloramphenicol, oxazolidinones, pleuromutilins and fusidic acid. There are two oxaborole-type leucine tRNA synthetase (LeuRS) inhibitors, epetraborole ( 13 ) and GSK3036656 ( 52 ), and one methionyl-tRNA synthetase inhibitor, CRS3123 ( 28 ), in clinical trials. The only marketed inhibitor of a tRNA synthetase is mupirocin, which targets isoleucyl-tRNA synthetase.

There are two direct-acting traditional and five non-traditional antibacterial compounds with new mechanisms. Telacebec ( 31 ) is an inhibitor of the mycobacterial respiratory cytochrome bc 1 complex [ 185 , 186 , 369 ]. Inhibition of bacterial respiratory systems is an emerging MoA [ 369 , 370 ] with three bedaquiline analogs, sudapyridine ( 38 ), TBAJ-876 ( 55 ) and TBAJ-587 ( 56 ) that are also in clinical development. GSK2556286 ( 57 ) was recently disclosed to be an adenylyl cyclase Rv1625c agonist, which interferes with cholesterol catabolism and reduces the levels of this critical carbon source [ 304 ]. RG6006 is a new antibacterial class but there is only limited public information available about the structure and MoA. There are three antivirulence compounds that employ totally different anti-virulence mechanisms: fluorothyazinone ( 40 ) inhibits the G-ve type III secretion system, GSK3882347 inhibits the binding of E. coli to host cell walls via FimH and ALS4 inhibits 4,4ʹ-diapophytoene desaturase (CrtN), which is an enzyme involved in the biosynthesis of staphyloxanthin. Finally, BVL-GSK098 ( 58 ) inactivates the TetR-like repressor, which reduces resistance to the TB drug ethionamide ( 59 ) and rescues its activity, which is conceptually similar to how BLIs restore the activity of BL antibiotics.

Administration analysis

The administration routes (po, oral; IV/po, intravenous oral switch; IV, intravenous; IV/topical, IV and topical; po topical, CDI oral; topical; inhalation; n/d, not disclosed) of the small molecule antibacterial compounds under clinical development were analyzed by development phase (Fig.  S1 ) and lead source (Fig.  S1 ). Oral administration predominates and 19 of the 30 (~63%) are being developed against mycobacteria, which is pivotal as anti-TB drug combinations are taken for multiple months and are often administered in countries with limited capacity to deliver IV treatments. The second highest category is IV administration with 15, while there are four candidates that can be used both IV and po and two for both IV and topical. This IV/oral switch strategy is a competitive advantage as it can be implemented when patients move from hospital-based IV administration to oral administration in wards or at home. Four candidates are being trialed using the po topical administration route, which is used to treat gastrointestinal infections, such as C. difficile and H. pylori . For these infections, drugs are usually orally administered, but most are not significantly systemically absorbed, which reduces the potential for toxicity; however, one of the CDI clinical candidates, DNV-3837 ( 25 ) is being investigated using IV administration. There are four topically-only administered candidates, while murepavadin ( 49 ) is being trialed with inhaled administration to treat P. aeruginosa infections in the lungs of cystic fibrosis patients. This is being undertaken to more efficiently deliver 49 into the lungs, but it may also ameliorate kidney toxicity that was observed in a prior nosocomial pneumonia trial [ 273 ].

Conclusion and outlook

The shape of the antibacterial pipeline has changed since our first analysis in 2011 [ 26 ]. At the front-end of the pipeline, there are now more than double the number of phase-I candidates (26) compared to 11 in 2015 [ 24 ] (Fig.  15 ). Funding initiatives have also helped to boost the number of phase-II (25) compounds since 2019 (18) (Fig.  15 ). Encouragingly, 16/26 (62%) of the compounds in phase-I and 14/25 (56%) in phase-II contain new pharmacophores (Figs.  16 and 17 ), with some also having new MoA (Table  8 ). Small molecule non-traditional antibacterial candidates are also starting to move through the pipeline with five in active development: fluorothyazinone ( 40 ), dovramilast ( 42 ), BVL-GSK098 ( 58 ), GSK3882347 and ALS4. Due to the increasing number of compounds with novel pharmacophores and targets in the pipeline (Table  8 , Figs.  16 and 17 ), it is more likely that novel antibacterial drug classes will enter the clinic in the next few years, which is preferable to just expanding the pool of ‘me-too’ antibiotics. However, despite these early stage improvements, it is sobering to note that the overall antibacterial pipeline is still sparse compared to other therapeutic indications such as oncology (2,335 clinical trials in 2021 [ 371 ]) and even COVID-19 vaccines (180 in the pipeline in February 2023 [ 372 ]).

In contrast to the early-stage pipeline, the late-stage pipeline is still experiencing issues. There were only two new small molecule antibacterial drugs first approved between 2020 and 2022 (Table  1 , Fig.  2 ): the fluoroquinolone levonadifloxacin ( 1 ) and its prodrug 2 in India in 2020 and the oxazolidinone contezolid ( 4 ) in China in 2021. There was also one ‘non-traditional’ live biotherapeutic product, Rebyota, approved in the USA in 2022 (Table  2 ). The last first-in-class small molecule approval was the anti-TB diarylquinoline bedaquiline in 2012. However, this could change, if the current phase-III candidates, gepotidacin ( 10 ), zoliflodacin ( 11 ) and epetraborole ( 13 ) (Table  3 , Fig.  4 ), all of which have new pharmacophores, were granted approval to treat gonorrhea and G-ve bacteria, gonorrhea, and M. avium complex (MAC) infections respectively. A future approval of the durlobactam ( 60 ) + sulbactam ( 61 ) combination for the treatment of A. baumannii-calcoaceticus (ABC) complex infections would also be a welcome addition to the antibacterial armamentarium. There has also been a steady but small decline in the number of phase-III candidates from 2013 to 2022 (Fig.  15 ). It will be critical to monitor how many of the phase-I and -II candidates, especially the compounds with new pharmacophores, move into Phase-III and beyond in the next few years.

In addition to the difficulty in identifying novel lead compounds suitable for antibacterial drug development, the ability to secure funding for phase-III trials and NDA/MAAs, as well as the capacity to generate adequate revenue to get positive net returns on investment for marketed antibacterial drugs [ 2 , 3 , 4 , 5 ], have been major obstacles to antibacterial drug development. Hopefully funding from organizations such as the AMR Action Fund [ 9 , 10 ] will help to ameliorate some of these funding issues, while the successful implementation of pull initiatives should help to improve financial returns [ 11 , 12 , 13 , 14 , 15 , 16 ]. Another welcome addition has been the US FDA’s Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD) pathway that provides the potential for smaller, shorter, or fewer clinical trials (at least two phase-III trials are usually required) if the antibacterial drug candidate is “intended to treat a serious or life-threatening infection in a limited population of patients with unmet needs” [ 373 ]. However, the approved drug then carries a label restricting its use, which could limit future sales.

At least 19/26 (73%) phase-I compounds target G-ve bacteria (12 traditional compounds, one anti-virulence and six BL/BLI combinations), with four of these also possessing anti-G+ve activity. The high percentage of G-ve candidates being developed mirrors the clinical need and the recent focus of most funding schemes; however, the addition of G+ve activity to the 2022/23 CARB-X funding calls reflects the high mortality observed for global G+ve resistant infections in 2019 [ 1 ]. Only six of these 17 traditional G-ve antibacterial candidates are administered orally, with four of these being BL/BLI prodrugs. Although NPs have traditionally been the main source of novel antibacterials, 23 of the 34 (68%) of the compounds with new antibacterial pharmacophores were synthetically derived. There are also a substantial number of antitubercular drugs (TB and NTM) in the pipeline (19/62 (31%); one in phase-III, 12 in phase-II, and six in phase-I), showing the success of targeted funding for neglected diseases through organizations such as the TB Alliance (New York, NY, USA) and the Bill & Melinda Gates Foundation (Seattle, WA, USA).

In conclusion, despite the encouraging trends in phase-I and -II antibacterial drug candidates and plans to address issues with the late-stage pipeline, it is not the time to relax the urgency to continue to stimulate further antibacterial drug discovery and development.

Change history

07 november 2023.

A Correction to this paper has been published: https://doi.org/10.1038/s41429-023-00671-6

https://www.fda.gov/news-events/press-announcements/fda-approves-first-orally-administered-fecal-microbiota-product-prevention-recurrence-clostridioides https://ir.serestherapeutics.com/news-releases/news-release-details/seres-therapeutics-and-nestle-health-science-announce-fda

https://www.empr.com/home/news/drugs-in-the-pipeline/fda-panel-in-favor-of-sulbactam-durlobactam-for-acinetobacter-infections/

Murray CJL, Ikuta KS, Sharara F, Swetschinski L, Robles Aguilar G, Gray A, et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022;399:629–55. https://doi.org/10.1016/S0140-6736(21)02724-0 .

Article   CAS   Google Scholar  

Shlaes DM. The economic conundrum for antibacterial drugs. Antimicrob Agents Chemother. 2019;64:e02057–19. https://doi.org/10.1128/AAC.02057-19 .

Article   PubMed   PubMed Central   Google Scholar  

McKenna M. The antibiotic paradox: why companies can’t afford to create life-saving drugs. Nature. 2020;584:338–41. https://doi.org/10.1038/d41586-020-02418-x .

Article   CAS   PubMed   Google Scholar  

Outterson K. Estimating the appropriate size of global pull incentives for antibacterial medicines. Health Aff. 2021;40:1758–65. https://doi.org/10.1377/hlthaff.2021.00688 .

Article   Google Scholar  

Madden J, Outterson K. Trends in the global antibiotics market. Nat Rev Drug Disco. 2023;22:174. https://doi.org/10.1038/d41573-023-00029-5 .

Alm RA, Gallant K. Innovation in antimicrobial resistance: the CARB-X perspective. ACS Infect Dis. 2020;6:1317–22. https://doi.org/10.1021/acsinfecdis.0c00026 .

Alt S, Haggstrom D, Kessmann H, Kloss F, Schneider CE, Jäger T, et al. INCATE: a partnership to boost the antibiotic pipeline. Nat Rev Drug Disco. 2022;21:621–2. https://doi.org/10.1038/d41573-022-00138-7 .

Engel A. Fostering antibiotic development through impact funding. ACS Infect Dis. 2020;6:1311–2. https://doi.org/10.1021/acsinfecdis.0c00069 .

McCall B. New fund stimulates the ailing antibiotic pipeline. Lancet Infect Dis. 2020;20:1017. https://doi.org/10.1016/S1473-3099(20)30629-0 .

Article   CAS   PubMed   PubMed Central   Google Scholar  

Mullard A. Pharmaceutical firms commit US$1 billion to antibiotic development. Nat Rev Drug Disco. 2020;19:575–6. https://doi.org/10.1038/d41573-020-00143-8 .

Mullard A. Pull incentives for antibiotics get push from the UK. Nat Rev Drug Disco. 2022;21:406. https://doi.org/10.1038/d41573-022-00088-0 .

Glover RE, Singer AC, Roberts AP, Kirchhelle C. The antibiotic subscription model: fostering innovation or repackaging old drugs. Lancet Microbe. 2023;4:e2–e3. https://doi.org/10.1016/S2666-5247(22)00235-X .

Article   PubMed   Google Scholar  

Leonard C, Crabb N, Glover D, Cooper S, Bouvy J, Wobbe M et al. Can the UK ‘Netflix’ Payment Model Boost The Antibacterial Pipeline? Appl Health Econ Health Policy. 2023;21. https://doi.org/10.1007/s40258-022-00786-1 .

Silverman R, Towse A. An ambitious USG advanced commitment for subscription-based purchasing of novel antimicrobials and its expected return on investment Washington DC, USA: Center for Global Development; 2021 [Accessed 24 January 2023]. Available from: https://www.cgdev.org/publication/ambitious-usg-advanced-commitment-subscription-based-purchasing-novel-antimicrobials .

The Pioneering Antimicrobial Subscriptions To End Up surging Resistance Act of 2021 or the PASTEUR Act of 2021; 2021 [Accessed 24 January 2023]. Available from: https://www.congress.gov/bill/117th-congress/house-bill/3932 .

Dall C. For PASTEUR Act advocates, the finish line is in sight for antibiotic development aid 2022 [Accessed 24 January 2023]. Available from: https://www.cidrap.umn.edu/antimicrobial-stewardship/pasteur-act-advocates-finish-line-sight-antibiotic-development-aid .

Theuretzbacher U, Piddock LJV. Non-traditional antibacterial therapeutic options and challenges. Cell Host Microbe. 2019;26:61–72. https://doi.org/10.1016/j.chom.2019.06.004 .

Shlaes DM. Innovation, nontraditional antibacterial drugs, and clinical utility. ACS Infect Dis. 2021;7:2027–8. https://doi.org/10.1021/acsinfecdis.1c00227 .

Rex JH, Fernandez Lynch H, Cohen IG, Darrow JJ, Outterson K. Designing development programs for non-traditional antibacterial agents. Nat Commun. 2019;10:3416. https://doi.org/10.1038/s41467-019-11303-9 .

Duffy EM, Buurman ET, Chiang SL, Cohen NR, Uria-Nickelsen M, Alm RA. The CARB-X portfolio of nontraditional antibacterial products. ACS Infect Dis. 2021;7:2043–9. https://doi.org/10.1021/acsinfecdis.1c00331 .

Butler MS, Gigante V, Sati H, Paulin S, Al-Sulaiman L, Rex JH, et al. Analysis of the clinical pipeline of treatments for drug-resistant bacterial infections: despite progress, more action is needed. Antimicrob Agents Chemother. 2022;66:e01991–21. https://doi.org/10.1128/aac.01991-21 .

World Health Organization. 2021 Antibacterial agents in clinical and preclinical development: an overview and analysis. World Health Organization: Geneva, Switzerland, 2022. Available from: https://www.who.int/publications/i/item/9789240047655 .

Butler MS, Paterson DL. Antibiotics in the clinical pipeline in October 2019. J Antibiot. 2020;73:329–64. https://doi.org/10.1038/s41429-020-0291-8 .

Butler MS, Blaskovich MAT, Cooper MA. Antibiotics in the clinical pipeline at the end of 2015. J Antibiot. 2017;70:3–24. https://doi.org/10.1038/ja.2016.72 .

Butler MS, Blaskovich MA, Cooper MA. Antibiotics in the clinical pipeline in 2013. J Antibiot. 2013;66:571–91. https://doi.org/10.1038/ja.2013.86 .

Butler MS, Cooper MA. Antibiotics in the clinical pipeline in 2011. J Antibiot. 2011;64:413–25. https://doi.org/10.1038/ja.2011.44 .

Pew Trusts. Analysis shows continued deficiencies in antibiotic development since 2014. Visualization tool lets users track changes in the pipeline from 2014 [Accessed 24 January 2023]. Available from: https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2019/five-year-analysis-shows-continued-deficiencies-in-antibiotic-development .

Pew Trusts. Tracking the global pipeline of antibiotics in development, March 2021 [Accessed 24 January 2023]. Available from: https://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2021/03/tracking-the-global-pipeline-of-antibiotics-in-development .

Frost I, Sati H, Garcia-Vello P, Hasso-Agopsowicz M, Lienhardt C, Gigante V, et al. The role of bacterial vaccines in the fight against antimicrobial resistance: an analysis of the preclinical and clinical development pipeline. Lancet Microbe. 2023;4:e113–e25. https://doi.org/10.1016/S2666-5247(22)00303-2 .

Prasad Neha K, Seiple Ian B, Cirz Ryan T, Rosenberg Oren S. Leaks in the pipeline: a failure analysis of Gram-negative antibiotic development from 2010 to 2020. Antimicrob Agents Chemother. 2022;66:e00054–22. https://doi.org/10.1128/aac.00054-22 .

Theuretzbacher U, Bush K, Harbarth S, Paul M, Rex JH, Tacconelli E, et al. Critical analysis of antibacterial agents in clinical development. Nat Rev Microbiol. 2020;18:286–98. https://doi.org/10.1038/s41579-020-0340-0 .

Theuretzbacher U, Outterson K, Engel A, Karlén A. The global preclinical antibacterial pipeline. Nat Rev Microbiol. 2020;18:275–85. https://doi.org/10.1038/s41579-019-0288-0 .

Vila J, Moreno-Morales J, Ballesté-Delpierre C. Current landscape in the discovery of novel antibacterial agents. Clin Microbiol Infect. 2020;26:596–603. https://doi.org/10.1016/j.cmi.2019.09.015 .

Jiménez MC, Kowalski L, Souto RB, Alves IA, Viana MD, Aragón DM. New drugs against multidrug-resistant Gram-negative bacteria: a systematic review of patents. Future Microbiol. 2022;17:1393–408. https://doi.org/10.2217/fmb-2022-0104 .

Si Z, Pethe K, Chan-Park MB. Chemical basis of combination therapy to combat antibiotic resistance. JACS Au. 2023;3:276–92. https://doi.org/10.1021/jacsau.2c00532 .

Walesch S, Birkelbach J, Jézéquel G, Haeckl FPJ, Hegemann JD, Hesterkamp T, et al. Fighting antibiotic resistance—strategies and (pre)clinical developments to find new antibacterials. EMBO Rep. 2023;24:e56033. https://doi.org/10.15252/embr.202256033 .

Editorial. C difficile−a rose by any other name. Lancet Infect Dis. 2019;19:449. https://doi.org/10.1016/S1473-3099(19)30177-X .

Médecins Sans Frontières. Bedaquiline: First new tuberculosis drug in 50 years (Press release 31 December 2012). 2012 [Accessed 27 January 2023]. Available from: https://www.msf.org/bedaquiline-first-new-tuberculosis-drug-50-years .

de Souza NJ, Gupte SV, Deshpande PK, Desai VN, Bhawsar SB, Yeole RD, et al. A chiral benzoquinolizine-2-carboxylic acid arginine salt active against vancomycin-resistant Staphylococcus aureus . J Med Chem. 2005;48:5232–42. https://doi.org/10.1021/jm050035f .

Veeraraghavan B, Bakthavatchalam YD, Manesh A, Lal B, Swaminathan S, Ansari A, et al. India-discovered levonadifloxacin & alalevonadifloxacin: A review on susceptibility testing methods, CLSI quality control and breakpoints along with a brief account of their emerging therapeutic profile as a novel standard-of-care. Indian J Med Microbiol. 2023;41:71–80. https://doi.org/10.1016/j.ijmmb.2022.11.005 .

Bhagwat S, Nandanwar M, Kansagara A, Patel A, Takalkar S, Chavan R, et al. Levonadifloxacin, a novel broad-spectrum anti-MRSA benzoquinolizine quinolone agent: review of current evidence. Drug Des Devel Ther. 2019;13:4351–65. https://doi.org/10.2147/DDDT.S229882 .

India’s First New Discovery Antibiotics from Wockhardt Granted Indian Regulatory Approval (Press release 16 January 2020) [Accessed 16 December 2022]. Available from: http://www.wockhardt.com/pdfs/Press-Release-16-01-2020.pdf .

Bhatia A, Mastim M, Shah M, Gutte R, Joshi P, Kumbhar D, et al. Efficacy and safety of a novel broad-spectrum anti-MRSA agent levonadifloxacin compared with linezolid for acute bacterial skin and skin structure infections: a phase 3, openlabel, randomized study. J Assoc Physicians India. 2020;68:30–6.

CAS   PubMed   Google Scholar  

Mehta Y, Sutar AR, Zirpe K, Kothari JN, Alapati C, Pathak M, et al. Prescription-event monitoring study on safety and efficacy of levonadifloxacin (oral and I.V.) in management of bacterial infections: findings of real-world observational study. Int J Appl Basic Med Res. 2022;12:30–6. https://doi.org/10.4103/ijabmr.ijabmr_602_21 .

Jacobs MR, Appelbaum PC. Nadifloxacin: a quinolone for topical treatment of skin infections and potential for systemic use of its active isomer, WCK 771. Expert Opin Pharmacother. 2006;7:1957–66. https://doi.org/10.1517/14656566.7.14.1957 .

China NMPA approves MicuRx’s contezolid for treatment of drug-resistant bacterial infection (Press release 2 June 2021) [Accessed 16 December 2022]. Available from: https://www.micurx.com/703.html .

Hoy SM. Contezolid: first approval. Drugs. 2021;81:1587–91. https://doi.org/10.1007/s40265-021-01576-0 .

Zhao X, Huang H, Yuan H, Yuan Z, Zhang Y. A Phase III multicentre, randomized, double-blind trial to evaluate the efficacy and safety of oral contezolid versus linezolid in adults with complicated skin and soft tissue infections. J Antimicrob Chemother. 2022;77:1762–9. https://doi.org/10.1093/jac/dkac073 .

Gordeev MF, Yuan ZYY. New potent antibacterial oxazolidinone (MRX-I) with an improved class safety profile. J Med Chem. 2014;57:4487–97. https://doi.org/10.1021/jm401931e .

Liu J, Wang W, Wang C, Zhang L, Zhang X, Liu S, et al. Discovery of antibacterial contezolid acefosamil: innovative O -acyl phosphoramidate prodrug for IV and oral therapies. ACS Med Chem Lett. 2022;13:1030–5. https://doi.org/10.1021/acsmedchemlett.2c00191 .

Greig SL. Obiltoxaximab: first global approval. Drugs. 2016;76:823–30. https://doi.org/10.1007/s40265-016-0577-0 .

Xu W, Ohanjandian L, Sun J, Cui X, Suffredini D, Li Y, et al. A systematic review and meta-analysis of preclinical trials testing anti-toxin therapies for B. anthracis infection: a need for more robust study designs and results. PLoS One. 2017;12:e0182879. https://doi.org/10.1371/journal.pone.0182879 .

Tsai C-W, Morris S. Approval of raxibacumab for the treatment of inhalation anthrax under the US Food and Drug Administration “Animal Rule”. Front Microbiol. 2015;6:1320. https://doi.org/10.3389/fmicb.2015.01320 .

Kufel WD, Devanathan AS, Marx AH, Weber DJ, Daniels LM. Bezlotoxumab: a novel agent for the prevention of recurrent Clostridium difficile infection. Pharmacotherapy. 2017;37:1298–308. https://doi.org/10.1002/phar.1990 .

Granata G, Schiavone F, Pipitone G. Bezlotoxumab in patients with a primary Clostridioides difficile  infection: a literature review. Antibiotics. 2022;11:1495. https://doi.org/10.3390/antibiotics11111495 .

Kelly CP, Poxton IR, Shen J, Wilcox MH, Gerding DN, Zhao X, et al. Effect of endogenous Clostridioides difficile toxin antibodies on recurrence of C. difficile infection. Clin Infect Dis. 2020;71:81–6. https://doi.org/10.1093/cid/ciz809 .

Johnson S, Citron DM, Gerding DN, Wilcox MH, Goldstein EJC, Sambol SP, et al. Efficacy of bezlotoxumab in trial participants infected with Clostridioides difficile strain BI associated with poor outcomes. Clin Infect Dis. 2021;73:e2616–e24. https://doi.org/10.1093/cid/ciaa1035 .

Ferring receives U.S. FDA approval for REBYOTA™ (fecal microbiota, live-jslm) – a novel first-in-class microbiota-based live biotherapeutic (Press release 30 November 2022) [Accessed 16 December 2022]. Available from: https://ferringusa.com/?press=ferring-receives-u-s-fda-approval-for-rebyota-fecal-microbiota-live-jslm-a-novel-first-in-class-microbiota-based-live-biotherapeutic .

Khanna S, Assi M, Lee C, Yoho D, Louie T, Knapple W, et al. Efficacy and safety of RBX2660 in PUNCH CD3, a Phase III, randomized, double-blind, placebo-controlled trial with a bayesian primary analysis for the prevention of recurrent Clostridioides difficile infection. Drugs. 2022;82:1527–38. https://doi.org/10.1007/s40265-022-01797-x .

Ray A, Jones C. Does the donor matter? Donor vs patient effects in the outcome of a next-generation microbiota-based drug trial for recurrent Clostridium difficile infection. Future Microbiol. 2016;11:611–6. https://doi.org/10.2217/fmb.16.10 .

Orenstein R, Dubberke E, Hardi R, Ray A, Mullane K, Pardi DS, et al. Safety and durability of RBX2660 (microbiota suspension) for recurrent Clostridium difficile infection: Results of the PUNCH CD study. Clin Infect Dis. 2015;62:596–602. https://doi.org/10.1093/cid/civ938 .

Donald B, Surani S, Deol H, Mbadugha U, Udeani G. Spotlight on solithromycin in the treatment of community-acquired bacterial pneumonia: design, development, and potential place in therapy. Drug Des Devel Ther. 2017;11:3559–66. https://doi.org/10.2147/DDDT.S119545 .

FUJIFILM Toyama Chemical Co., Ltd. Pipeline (as of Nov. 2022) [Accessed 16 December 2022]. Available from: https://www.fujifilm.com/fftc/en/about/rd/pipeline .

Fierce Biotech. Cempra pulls EU antibiotic filing following EMA questioning (28 March 2017) [Accessed 16 December 2022]. Available from: https://www.fiercebiotech.com/biotech/cempra-pulls-eu-antibiotic-filing-following-ema-questioning .

Minamimura M, Taniyama Y, Inoue E, Mitsuhashi S. In vitro antibacterial activity and β-lactamase stability of CP-70,429 a new penem antibiotic. Antimicrob Agents Chemother. 1993;37:1547–51. https://doi.org/10.1128/AAC.37.7.1547 .

Foulds G, Knirsch AK, Lazar JD, Tensfelt TG, Gerber N. Pharmacokinetics of the penem CP-65,207 and its separate stereoisomers in humans. Antimicrob Agents Chemother. 1991;35:665–71. https://doi.org/10.1128/AAC.35.4.665 .

Brenek SJ, Caron S, Chisowa E, Delude MP, Drexler MT, Ewing MD, et al. Development of a practical and convergent process for the preparation of sulopenem. Org Process Res Dev. 2012;16:1348–59. https://doi.org/10.1021/op300131e .

Brenek SJ, Caron S, Chisowa E, Colon-Cruz R, Delude MP, Drexler MT, et al. Development of a second-generation process to antibacterial candidate sulopenem. Org Process Res Dev. 2012;16:1338–47. https://doi.org/10.1021/op300130p .

Dunne MW, Aronin SI, Das AF, Akinapelli K, Breen J, Zelasky MT, et al. Sulopenem for the treatment of complicated urinary tract infections including pyelonephritis: a phase 3, randomized trial. Clin Infect Dis. 2023;76:78–88. https://doi.org/10.1093/cid/ciac704 .

Dunne MW, Aronin SI, Das AF, Akinapelli K, Zelasky MT, Puttagunta S, et al. Sulopenem or ciprofloxacin for the treatment of uncomplicated urinary tract infections in women: a phase 3, randomized trial. Clin Infect Dis. 2023;76:66–77. https://doi.org/10.1093/cid/ciac738 .

Iterum Therapeutics announces U.S. FDA filing acceptance of New Drug Application for oral sulopenem (Press release 25 January 2021) [Accessed 16 December 2022]. Available from: https://www.iterumtx.com/news/press-releases/detail/58/iterum-therapeutics-announces-u-s-fda-filing-acceptance-of .

Dunne M, Dunzo E, Puttagunta S. A phase 1 study to assess the pharmacokinetics of sulopenem etzadroxil (PF-03709270). Open Forum Infect Dis. 2017;4:S525–S6. https://doi.org/10.1093/ofid/ofx163.1369 .

Cox VC, Zed PJ. Once-daily cefazolin and probenecid for skin and soft tissue infections. Ann Pharmacother. 2004;38:458–63. https://doi.org/10.1345/aph.1D2 .

Iterum Therapeutics receives Complete Response Letter from U.S. Food and Drug Administration for oral sulopenem (Press release 26 July 2021) [Accessed 16 December 2022]. Available from: https://www.iterumtx.com/news/press-releases/detail/73/iterum-therapeutics-receives-complete-response-letter-from .

Rodvold KA, Gotfried MH, Chugh R, Gupta M, Friedland HD, Bhatia A. Comparison of plasma and intrapulmonary concentrations of nafithromycin (WCK 4873) in healthy adult subjects. Antimicrob Agents Chemother. 2017;61:e01096–17. https://doi.org/10.1128/aac.01096-17 .

Hackel MA, Karlowsky JA, Dressel D, Sahm DF. Determination of disk diffusion and MIC quality control ranges for nafithromycin (WCK 4873), a new lactone-ketolide. J Clin Microbiol. 2017;55:3021–7. https://doi.org/10.1128/JCM.00972-17 .

Zhou M, Wu L, Kang W, Li Y, Zhang G, Zhang J, et al. In vitro activity of lactone ketolide nafithromycin (WCK 4873) against Streptococcus pneumoniae isolates enriched with macrolide-resistance phenotype collected from mainland China. JAC Antimicrob Resist 2022;4:dlac103. https://doi.org/10.1093/jacamr/dlac103 .

Kohlhoff S, Hammerschlag MR. In vitro activity of nafithromycin (WCK 4873) against Chlamydia pneumoniae . Antimicrob Agents Chemother. 2021;65:e00585–21. https://doi.org/10.1128/AAC.00585-21 .

Gibson EG, Bax B, Chan PF, Osheroff N. Mechanistic and structural basis for the actions of the antibacterial gepotidacin against Staphylococcus aureus gyrase. ACS Infect Dis. 2019;5:570–81. https://doi.org/10.1021/acsinfecdis.8b00315 .

EAGLE-2 and EAGLE-3 phase III trials for gepotidacin stopped early for efficacy following pre-planned interim analysis by Independent Data Monitoring Committee (Press release 3 November 2022) [Accessed 17 December 2022]. Available from: https://www.gsk.com/en-gb/media/press-releases/gsk-announces-phase-iii-trials-for-gepotidacin/ .

Flamm RK, Farrell DJ, Rhomberg PR, Scangarella-Oman NE, Sader HS. Gepotidacin (GSK2140944) in vitro activity against Gram-positive and Gram-negative bacteria. Antimicrob Agents Chemother. 2017;61:e00468–17. https://doi.org/10.1128/aac.00468-17 .

Biedenbach DJ, Bouchillon SK, Hackel M, Miller LA, Scangarella-Oman NE, Jakielaszek C, et al. In vitro activity of gepotidacin, a novel triazaacenaphthylene bacterial topoisomerase inhibitor, against a broad spectrum of bacterial pathogens. Antimicrob Agents Chemother. 2016;60:1918–23. https://doi.org/10.1128/AAC.02820-15 .

Hackel MA, Karlowsky JA, Canino MA, Sahm DF, Scangarella-Oman NE. In vitro activity of gepotidacin against Gram-negative and Gram-positive anaerobes. Antimicrob Agents Chemother. 2022;66:e02165–21. https://doi.org/10.1128/aac.02165-21 .

Ahmad MN, Garg T, Singh S, Shukla R, Malik P, Krishnamurthy RV, et al. In vitro and in vivo activity of gepotidacin against drug-resistant mycobacterial infections. Antimicrob Agents Chemother. 2022;66:e00564–22. https://doi.org/10.1128/aac.00564-22 .

Sanders MI, Ali E, Buer J, Steinmann J, Rath P-M, Verhasselt HL, et al. Antibacterial activity of the novel drug gepotidacin against Stenotrophomonas maltophilia − an in vitro and in vivo study. Antibiotics. 2022;11:192. https://doi.org/10.3390/antibiotics11020192 .

Waites KB, Crabb DM, Xiao L, Duffy LB. In vitro activities of gepotidacin (GSK2140944) and other antimicrobial agents against Human mycoplasmas and ureaplasmas. Antimicrob Agents Chemother. 2017;61:e01064–17. https://doi.org/10.1128/aac.01064-17 .

Kern G, Palmer T, Ehmann DE, Shapiro AB, Andrews B, Basarab GS, et al. Inhibition of Neisseria gonorrhoeae type II topoisomerases by the novel spiropyrimidinetrione AZD0914. J Biol Chem. 2015;290:20984–94. https://doi.org/10.1074/jbc.M115.663534 .

Innoviva Completes Acquisition of Entasis Therapeutics (Press release 11 July 2022) [Accessed 17 December 2022]. Available from: https://investor.inva.com/news-releases/news-release-details/innoviva-completes-acquisition-entasis-therapeutics .

Jacobsson S, Golparian D, Alm RA, Huband M, Mueller J, Jensen JS, et al. High in vitro activity of the novel spiropyrimidinetrione AZD0914, a DNA gyrase inhibitor, against multidrug-resistant Neisseria gonorrhoeae isolates suggests a new effective option for oral treatment of gonorrhea. Antimicrob Agents Chemother. 2014;58:5585–8. https://doi.org/10.1128/AAC.03090-14 .

Unemo M, Ahlstrand J, Sánchez-Busó L, Day M, Aanensen D, Golparian D, et al. High susceptibility to zoliflodacin and conserved target (GyrB) for zoliflodacin among 1209 consecutive clinical Neisseria gonorrhoeae isolates from 25 European countries, 2018. J Antimicrob Chemother. 2021;76:1221–8. https://doi.org/10.1093/jac/dkab024 .

Taylor SN, Marrazzo J, Batteiger BE, Hook EW, Seña AC, Long J, et al. Single-dose zoliflodacin (ETX0914) for treatment of urogenital gonorrhea. N Engl J Med. 2018;379:1835–45. https://doi.org/10.1056/NEJMoa1706988 .

GARDP website. Sexually Transmitted Infections, Zoliflodacin drug development project [Accessed 17 December 2022]. Available from: https://gardp.org/sexually-transmitted-infections/ .

Damião Gouveia AC, Unemo M, Jensen JS. In vitro activity of zoliflodacin (ETX0914) against macrolide-resistant, fluoroquinolone-resistant and antimicrobial-susceptible Mycoplasma genitalium strains. J Antimicrob Chemother. 2018;73:1291–4. https://doi.org/10.1128/aac.00564-22 .

Zhao C-Y, Lv Y, Zhu Y, Wei M-J, Liu M-Y, Ji X-W, et al. A first-in-human safety, tolerability, and pharmacokinetics study of benapenem in healthy Chinese volunteers. Antimicrob Agents Chemother. 2019;63:e02188–18. https://doi.org/10.1128/aac.02188-18 .

Yang H, Zhang M, Chen Y, Ren H, Zhang H, Yu C, et al. Pharmacokinetics of benapenem for injection in subjects with mild to moderate renal impairment. Eur J Clin Pharm. 2022;78:1079–86. https://doi.org/10.1007/s00228-022-03317-y .

Hernandez V, Crépin T, Palencia A, Cusack S, Akama T, Baker SJ, et al. Discovery of a novel class of boron-based antibacterials with activity against Gram-negative bacteria. Antimicrob Agents Chemother. 2013;57:1394–403. https://doi.org/10.1128/AAC.02058-12 .

van Ingen J, Obradovic M, Hassan M, Lesher B, Hart E, Chatterjee A, et al. Nontuberculous mycobacterial lung disease caused by Mycobacterium avium complex - disease burden, unmet needs, and advances in treatment developments. Expert Rev Respir Med. 2021;15:1387–401. https://doi.org/10.1080/17476348.2021.1987891 .

Ganapathy US, Gengenbacher M, Dick T. Epetraborole is active against Mycobacterium abscessus . Antimicrob Agents Chemother. 2021;65:e01156–21. https://doi.org/10.1128/AAC.01156-21 .

Sullivan JR, Lupien A, Kalthoff E, Hamela C, Taylor L, Munro KA, et al. Efficacy of epetraborole against Mycobacterium abscessus is increased with norvaline. PLoS Pathog. 2021;17:e1009965. https://doi.org/10.1371/journal.ppat.1009965 .

O’Dwyer K, Spivak AT, Ingraham K, Min S, Holmes DJ, Jakielaszek C, et al. Bacterial resistance to leucyl-tRNA synthetase inhibitor GSK2251052 develops during treatment of complicated urinary tract infections. Antimicrob Agents Chemother. 2015;59:289–98. https://doi.org/10.1128/AAC.03774-14 .

Brii Biosciences Pipeline [Accessed 2 January 2023]. Available from: https://www.briibio.com/en/science/pipeline/ .

Tamura S, Miyazaki S, Tateda K, Ohno A, Ishii Y, Matsumoto T, et al. In vivo antibacterial activities of sanfetrinem cilexetil, a new oral tricyclic antibiotic. Antimicrob Agents Chemother. 1998;42:1858–61. https://doi.org/10.1128/AAC.42.7.1858 .

Doern GV, Pierce G, Brueggemann AB. In vitro activity of sanfetrinem (GV104326), a new trinem antimicrobial agent, versus Streptococcus pneumoniae , Haemophilus influenzae , and Moraxella catarrhalis . Diagn Microbiol Infect Dis. 1996;26:39–42. https://doi.org/10.1016/S0732-8893(96)00173-3 .

Sader HS, Gales AC. Emerging strategies in infectious diseases. Drugs. 2001;61:553–64. https://doi.org/10.2165/00003495-200161050-00001 .

Working Group on TB Drugs Pipeline - Sanfertrinem [Accessed 21 December 2022]. Available from: https://www.newtbdrugs.org/pipeline/compound/sanfetrinem .

Diacon AH, van der Merwe L, Barnard M, von Groote-Bidlingmaier F, Lange C, García-Basteiro AL, et al. β-Lactams against tuberculosis — new trick for an old dog. N Engl J Med. 2016;375:393–4. https://doi.org/10.1056/NEJMc1513236 .

Gold B, Zhang J, Quezada LL, Roberts J, Ling Y, Wood M, et al. Identification of β-lactams active against Mycobacterium tuberculosis by a consortium of pharmaceutical companies and academic institutions. ACS Infect Dis. 2022;8:557–73. https://doi.org/10.1021/acsinfecdis.1c00570 .

MGB Biopharma announces successful outcome from Phase II clinical study with MGB-BP-3 – a potential new gold standard, first-line treatment for Clostridium difficile infection (CDI) (Press release 19 May 2020) [Accessed 21 December 2022]. Available from: https://www.mgb-biopharma.com/mgb-biopharma-announces-successful-outcome-from-phase-ii-clinical-study-with-mgb-bp-3-a-potential-new-gold-standard-first-line-treatment-for-clostridium-difficile-infection-cdi/ .

Anthony NG, Breen D, Clarke J, Donoghue G, Drummond AJ, Ellis EM, et al. Antimicrobial lexitropsins containing amide, amidine, and alkene linking groups. J Med Chem. 2007;50:6116–25. https://doi.org/10.1021/jm070831g .

Suckling CJ. The antibacterial drug MGB-BP3: from discovery to clinical trial. Chem Biol Interface. 2015;5:166–74.

CAS   Google Scholar  

Hind C, Clifford M, Woolley C, Harmer J, McGee LMC, Tyson-Hirst I, et al. Insights into the spectrum of activity and mechanism of action of MGB-BP-3. ACS Infect Dis. 2022;8:2552–63. https://doi.org/10.1021/acsinfecdis.2c00445 .

Kerr L, Browning DF, Lemonidis K, Salih T, Hunter IS, Suckling CJ, et al. Novel antibiotic mode of action by repression of promoter isomerisation. bioRxiv. 2021. https://doi.org/10.1101/2020.12.31.424950 .

Kaushik V, Tiwari M, Tiwari V. Interaction of RecA mediated SOS response with bacterial persistence, biofilm formation, and host response. Int J Biol Macromol. 2022;217:931–43. https://doi.org/10.1016/j.ijbiomac.2022.07.176 .

Ooi N, Miller K, Hobbs J, Rhys-Williams W, Love W, Chopra I. XF-73, a novel antistaphylococcal membrane-active agent with rapid bactericidal activity. J Antimicrob Chemother. 2009;64:735–40. https://doi.org/10.1093/jac/dkp299 .

Farrell DJ, Robbins M, Rhys-Williams W, Love WG. In vitro activity of XF-73, a novel antibacterial agent, against antibiotic-sensitive and -resistant Gram-positive and Gram-negative bacterial species. Int J Antimicrob Agents. 2010;35:531–6. https://doi.org/10.1016/j.ijantimicag.2010.02.008 .

Ooi N, Miller K, Randall C, Rhys-Williams W, Love W, Chopra I. XF-70 and XF-73, novel antibacterial agents active against slow-growing and non-dividing cultures of Staphylococcus aureus including biofilms. J Antimicrob Chemother. 2010;65:72–8. https://doi.org/10.1093/jac/dkp409 .

MacLean RC. Assessing the potential for Staphylococcus aureus to evolve resistance to XF-73. Trends Microbiol. 2020;28:432–5. https://doi.org/10.1016/j.tim.2020.03.011 .

XF-73 nasal final Phase 3 development plans (Press release 7 December 2022) [Accessed 21 December 2022]. Available from: https://otp.tools.investis.com/clients/uk/destiny_pharma_ltd/rns/regulatory-story.aspx?cid=2241&newsid=1650054 .

van Klingeren B, ten Ham M. Antibacterial activity of Δ 9 -tetrahydrocannabinol and cannabidiol. Antonie van Leeuwenhoek. 1976;42:9–12. https://doi.org/10.1007/BF00399444 .

Appendino G, Gibbons S, Giana A, Pagani A, Grassi G, Stavri M, et al. Antibacterial cannabinoids from Cannabis sativa : A structure−activity study. J Nat Prod. 2008;71:1427–30. https://doi.org/10.1021/np8002673 .

Martinenghi LD, Jønsson R, Lund T, Jenssen H. Isolation, purification, and antimicrobial characterization of cannabidiolic acid and cannabidiol from Cannabis sativa L. Biomolecules. 2020;10:900. https://doi.org/10.3390/biom10060900 .

Blaskovich MAT, Kavanagh AM, Elliott AG, Zhang B, Ramu S, Amado M, et al. The antimicrobial potential of cannabidiol. Commun Biol. 2021;4:7. https://doi.org/10.1038/s42003-020-01530-y .

Wassmann CS, Rolsted AP, Lyngsie MC, Torres-Puig S, Kronborg T, Vestergaard M, et al. The menaquinone pathway is important for susceptibility of Staphylococcus aureus to the antibiotic adjuvant, cannabidiol. Microbiol Res. 2022;257:126974. https://doi.org/10.1016/j.micres.2022.126974 .

Choi S-R, Frandsen J, Narayanasamy P. Novel long-chain compounds with both immunomodulatory and MenA inhibitory activities against Staphylococcus aureus and its biofilm. Sci Rep. 2017;7:40077. https://doi.org/10.1038/srep40077 .

Johnston JM, Bulloch EMM. Advances in menaquinone biosynthesis: sublocalisation and allosteric regulation. Curr Opin Struct Biol. 2020;65:33–41. https://doi.org/10.1016/j.sbi.2020.05.005 .

Yuan Y, Wang X, Xu X, Liu Y, Li C, Yang M, et al. Evaluation of a dual-acting antibacterial agent, TNP-2092, on gut microbiota and potential application in the treatment of gastrointestinal and liver disorders. ACS Infect Dis. 2020;6:820–31. https://doi.org/10.1021/acsinfecdis.9b00374 .

TenNor reports positive Phase II results for TNP-2092 capsule (Press release 23 November 2021) [Accessed 21 December 2022]. Available from: http://www.tennorx.com/en/h-nd-86.html?fromColId=148 .

Fisher CR, Schmidt-Malan SM, Ma Z, Yuan Y, He S, Patel R. In vitro activity of TNP-2092 against periprosthetic joint infection–associated staphylococci. Diagn Microbiol Infect Dis. 2020;97:115040. https://doi.org/10.1016/j.diagmicrobio.2020.115040 .

Ma Z, Lynch AS. Development of a dual-acting antibacterial agent (TNP-2092) for the treatment of persistent bacterial infections. J Med Chem. 2016;59:6645–57. https://doi.org/10.1021/acs.jmedchem.6b00485 .

Robertson GT, Bonventre EJ, Doyle TB, Du Q, Duncan L, Morris TW, et al. In vitro evaluation of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic: microbiology profiling studies with Staphylococci and Streptococci. Antimicrob Agents Chemother. 2008;52:2324–34. https://doi.org/10.1128/AAC.01651-07 .

Robertson GT, Bonventre EJ, Doyle TB, Du Q, Duncan L, Morris TW, et al. In vitro evaluation of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic: studies of the mode of action in Staphylococcus aureus . Antimicrob Agents Chemother. 2008;52:2313–23. https://doi.org/10.1128/AAC.01649-07 .

Ma Z, He S, Yuan Y, Zhuang Z, Liu Y, Wang H, et al. Design, synthesis, and characterization of TNP-2198, a dual-targeted rifamycin-nitroimidazole conjugate with potent activity against microaerophilic and anaerobic bacterial pathogens. J Med Chem. 2022;65:4481–95. https://doi.org/10.1021/acs.jmedchem.1c02045 .

TenNor discloses TNP-2198 for the treatment of H. pylori Infections in the Journal of Medicinal Chemistry (Press release 18 February 2022) [Accessed 21 December 2022]. Available from: http://www.tennorx.com/en/h-nd-95.html .

Guangzhou Yushi Pharmaceutical Technology Co. Website [Accessed 21 December 2022]. Available from: https://www.yscro.com/search.html?q=TNP-2198 .

Payne DJ, Miller WH, Berry V, Brosky J, Burgess WJ, Chen E, et al. Discovery of a novel and potent class of FabI-directed antibacterial agents. Antimicrob Agents Chemother. 2002;46:3118–24. https://doi.org/10.1128/AAC.46.10.3118-3124.2002 .

Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Disco. 2007;6:29–40. https://doi.org/10.1038/nrd2201 .

Hafkin B, Kaplan N, Murphy B. Efficacy and safety of AFN-1252, the first Staphylococcus -specific antibacterial agent, in the treatment of acute bacterial skin and skin structure infections, including those in patients with significant comorbidities. Antimicrob Agents Chemother. 2015;60:1695–701. https://doi.org/10.1128/AAC.01741-15 .

Menetrey A, Janin A, Pullman J, Overcash JS, Haouala A, Leylavergne F, et al. Bone and joint tissue penetration of the Staphylococcus -selective antibiotic afabicin in patients undergoing elective hip replacement surgery. Antimicrob Agents Chemother. 2019;63:e01669–18. https://doi.org/10.1128/aac.01669-18 .

Wittke F, Vincent C, Chen J, Heller B, Kabler H, Overcash JS, et al. Afabicin, a first-in-class antistaphylococcal antibiotic, in the treatment of acute bacterial skin and skin structure infections: Clinical noninferiority to vancomycin/linezolid. Antimicrob Agents Chemother. 2020;64:e00250–20. https://doi.org/10.1128/AAC.00250-20 .

Parsons JB, Kukula M, Jackson P, Pulse M, Simecka JW, Valtierra D, et al. Perturbation of Staphylococcus aureus gene expression by the enoyl-acyl carrier protein reductase inhibitor AFN-1252. Antimicrob Agents Chemother. 2013;57:2182–90. https://doi.org/10.1128/AAC.02307-12 .

Kaplan N, Albert M, Awrey D, Bardouniotis E, Berman J, Clarke T, et al. Mode of action, in vitro activity, and in vivo efficacy of AFN-1252, a selective antistaphylococcal FabI inhibitor. Antimicrob Agents Chemother. 2012;56:5865–74. https://doi.org/10.1128/AAC.01411-12 .

Dyon-Tafani V, Josse J, Dieppois G, Ferry T, Laurent F. Antimicrobial activity of the new FabI inhibitor afabicin desphosphono against intraosteoblastic Staphylococcus aureus . Int J Antimicrob Agents. 2021;57:106321. https://doi.org/10.1016/j.ijantimicag.2021.106321 .

Rana P, Ghouse SM, Akunuri R, Madhavi YV, Chopra S, Nanduri S. FabI (enoyl acyl carrier protein reductase) - A potential broad spectrum therapeutic target and its inhibitors. Eur J Med Chem. 2020;208:112757. https://doi.org/10.1016/j.ejmech.2020.112757 .

Feng Q, Huang Y, Chen M, Li G, Chen Y. Functional synergy of α-helical antimicrobial peptides and traditional antibiotics against Gram-negative and Gram-positive bacteria in vitro and in vivo. Eur J Clin Microbiol Infect Dis. 2015;34:197–204. https://doi.org/10.1007/s10096-014-2219-3 .

Chen Y, Mant CT, Farmer SW, Hancock REW, Vasil ML, Hodges RS. Rational design of α-helical antimicrobial peptides with enhanced activities and specificity/therapeutic index. J Biol Chem. 2005;280:12316–29. https://doi.org/10.1074/jbc.M413406200 .

Wei Y, Wu J, Chen Y, Fan K, Yu X, Li X, et al. Efficacy and safety of PL-5 (peceleganan) spray for wound infections: A phase IIb randomized clinical trial. Ann Surg. 2023;277:43–9. https://doi.org/10.1097/SLA.0000000000005508 .

MST Access. Recce Pharmaceuticals (RCE.AX) Initiation of Coverage 2021 [Accessed 16 February 2023]. Available from: https://www.recce.com.au/PDF-Flip/Recce_iPoster.pdf .

Dilizia M, Tsunemoto H, Quach D, Sharp M, Prendergast J, Graham J. Elucidating the mechanism of action of novel polymer-based. Synthetic anti-infective compound RECCE® 327. 2021 [Accessed 16 February 2023]. Available from: https://www.recce.com.au/PDF-Flip/Recce_iPoster.pdf .

Folsom JP, Baker B, Stewart PS. In vitro efficacy of bismuth thiols against biofilms formed by bacteria isolated from human chronic wounds. J Appl Microbiol. 2011;111:989–96. https://doi.org/10.1111/j.1365-2672.2011.05110.x .

Baker B. 1289. Pravibismane is a potent, broad spectrum anti-infective small molecule that rapidly disrupts bacterial bioenergetics and halts bacterial growth. Open Forum Infect Dis. 2020;7:S659–S60. https://doi.org/10.1093/ofid/ofaa439.1472 .

Article   PubMed Central   Google Scholar  

Bierer DW. Bismuth subsalicylate: history, chemistry, and safety. Clin Infect Dis. 1990;12:S3–S8. https://doi.org/10.1093/clinids/12.supplement_1.s3 .

Barillo DJ, Barillo AR, Korn S, Lam K, Attar PS. The antimicrobial spectrum of Xeroform ® . Burns. 2017;43:1189–94. https://doi.org/10.1016/j.burns.2016.10.023 .

Alkim H, Koksal AR, Boga S, Sen I, Alkim C. Role of bismuth in the eradication of Helicobacter pylori . Am J Ther. 2017;24:e751–e7. https://doi.org/10.1136/gutjnl-2015-311019 .

Frei A, Zuegg J, Elliott AG, Baker M, Braese S, Brown C, et al. Metal complexes as a promising source for new antibiotics. Chem Sci. 2020;11:2627–39. https://doi.org/10.1039/C9SC06460E .

Frei A, Verderosa A, Elliott AG, Zuegg J, Blaskovich MAT. Metals to combat antimicrobial resistance. Nat Rev Chem. 2023;7:202–24. https://doi.org/10.1038/s41570-023-00463-4 .

DEINOVE is now ready to start Phase II clinical trial for its antibiotic compound DNV3837 (Press Release 16 May 2019) [Accessed 2 February 2023]. Available from: http://www.deinove.com/en/news/all-press-releases/deinove-now-ready-start-phase-ii-clinical-trial-its-antibiotic-compound-dnv3837 .

DEINOVE announces the opening of receivership proceedings (Press release 7 November 2022) [Accessed 22 December 2022]. Available from: https://www.deinove.com/en/news/all-press-releases/deinove-announces-opening-receivership-proceedings .

Rashid M-U, Dalhoff A, Weintraub A, Nord CE. In vitro activity of MCB3681 against Clostridium difficile strains. Anaerobe. 2014;28:216–9. https://doi.org/10.1016/j.anaerobe.2014.07.001 .

Rashid M-U, Dalhoff A, Bäckström T, Björkhem-Bergman L, Panagiotidis G, Weintraub A, et al. Ecological impact of MCB3837 on the normal human microbiota. Int J Antimicrob Agents. 2014;44:125–30. https://doi.org/10.1016/j.ijantimicag.2014.03.016 .

Dalhoff A, Rashid MU, Kapsner T, Panagiotidis G, Weintraub A, Nord CE. Analysis of effects of MCB3681, the antibacterially active substance of prodrug MCB3837, on human resident microflora as proof of principle. Clin Microbiol Infect. 2015;21:767.e1–.e4. https://doi.org/10.1016/j.cmi.2015.05.025 .

Wright GE, Brown NC, Xu W-C, Long Z-Y, Zhi C, Gambino JJ, et al. Active site directed inhibitors of replication-specific bacterial DNA polymerases. Bioorg Med Chem Lett. 2005;15:729–32. https://doi.org/10.1016/j.bmcl.2004.11.016 .

Xu W-C, Wright GE, Brown NC, Long Z-Y, Zhi C-X, Dvoskin S, et al. 7-Alkyl-N 2 -substituted-3-deazaguanines. Synthesis, DNA polymerase III inhibition and antibacterial activity. Bioorg Med Chem Lett. 2011;21:4197–202. https://doi.org/10.1016/j.bmcl.2011.05.093 .

Xu W-C, Silverman MH, Yu XY, Wright G, Brown N. Discovery and development of DNA polymerase IIIC inhibitors to treat Gram-positive infections. Bioorg Med Chem. 2019;27:3209–17. https://doi.org/10.1016/j.bmc.2019.06.017 .

Murray B, Wolfe C, Marra A, Pillar C, Shinabarger D. In vitro activity of the novel antibacterial agent ibezapolstat (ACX-362E) against Clostridioides difficile . J Antimicrob Chemother. 2020;75:2149–55. https://doi.org/10.1093/jac/dkaa134 .

Garey KW, McPherson J, Dinh AQ, Hu C, Jo J, Wang W, et al. Efficacy, safety, pharmacokinetics, and microbiome changes of ibezapolstat in adults with Clostridioides difficile infection: a phase 2a multicenter clinical trial. Clin Infect Dis. 2022;75:1164–70. https://doi.org/10.1093/cid/ciac096 .

Critchley IA, Green LS, Young CL, Bullard JM, Evans RJ, Price M, et al. Spectrum of activity and mode of action of REP3123, a new antibiotic to treat Clostridium difficile infections. J Antimicrob Chemother. 2009;63:954–63. https://doi.org/10.1093/jac/dkp041 .

Citron DM, Warren YA, Tyrrell KL, Merriam V, Goldstein EJC. Comparative in vitro activity of REP3123 against Clostridium difficile and other anaerobic intestinal bacteria. J Antimicrob Chemother. 2009;63:972–6. https://doi.org/10.1093/jac/dkp037 .

Ochsner UA, Bell SJ, O’Leary AL, Hoang T, Stone KC, Young CL, et al. Inhibitory effect of REP3123 on toxin and spore formation in Clostridium difficile , and in vivo efficacy in a hamster gastrointestinal infection model. J Antimicrob Chemother. 2009;63:964–71. https://doi.org/10.1093/jac/dkp042 .

Nayak SU, Griffiss JM, Blumer J, O’Riordan MA, Gray W, McKenzie R, et al. Safety, tolerability, systemic exposure, and metabolism of CRS3123, a methionyl-tRNA synthetase inhibitor developed for treatment of Clostridium difficile , in a Phase 1 study. Antimicrob Agents Chemother. 2017;61:e02760–16. https://doi.org/10.1128/AAC.02760-16 .

Lomeli BK, Galbraith H, Schettler J, Saviolakis GA, El-Amin W, Osborn B, et al. Multiple-ascending-dose phase 1 clinical study of the safety, tolerability, and pharmacokinetics of CRS3123, a narrow-spectrum agent with minimal disruption of normal gut microbiota. Antimicrob Agents Chemother. 2019;64:e01395–19. https://doi.org/10.1128/AAC.01395-19 .

Baedeker M, Ringel MS, Möller CC, Schulze U. 2022 FDA approval number dips: a COVID-19 hangover. Nat Rev Drug Disco. 2023;22:91. https://doi.org/10.1038/d41573-023-00007-x .

Jeong J-W, Jung S-J, Lee H-H, Kim Y-Z, Park T-K, Cho Y-L, et al. In vitro and in vivo activities of LCB01-0371, a new oxazolidinone. Antimicrob Agents Chemother. 2010;54:5359–62. https://doi.org/10.1128/AAC.00723-10 .

Zong Z, Jing W, Shi J, Wen SA, Zhang T, Huo F, et al. Comparison of in vitro activity and MIC distributions between the novel oxazolidinone delpazolid and linezolid against multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis in China. Antimicrob Agents Chemother. 2018;62:e00165–18. https://doi.org/10.1128/AAC.00165-18 .

Wang C, Wang G, Huo F, Xue Y, Jia J, Dong L et al. Novel oxazolidinones harbor potent in vitro activity against the clinical isolates of multidrug-resistant Mycobacterium tuberculosis in China. Front Med. 2022;9. https://doi.org/10.3389/fmed.2022.1067 .

Kim TS, Choe JH, Kim YJ, Yang C-S, Kwon H-J, Jeong J, et al. Activity of LCB01-0371, a novel oxazolidinone, against Mycobacterium abscessus . Antimicrob Agents Chemother. 2017;61:e02752–16. https://doi.org/10.1128/AAC.02752-16 .

Kim DH, Kim S-Y, Koh W-J, Jhun BW. In vitro activity of oxazolidinone against nontuberculous mycobacteria, including macrolide-resistant clinical isolates. Antimicrob Agents Chemother. 2021;65:e02306–20. https://doi.org/10.1128/AAC.02306-20 .

Donald PR, Sirgel FA, Venter A, Parkin DP, Seifart HI, van de Wal BW, et al. Early bactericidal activity of antituberculosis agents. Expert Rev Anti Infect Ther. 2003;1:141–55. https://doi.org/10.1586/14787210.1.1.141 .

Kim JS, Kim Y-h, Lee SH, Kim YH, Kim J-w, Kang JY, et al. Early bactericidal activity of delpazolid (LCB01-0371) in patients with pulmonary tuberculosis. Antimicrob Agents Chemother. 2022;66:e01684–21. https://doi.org/10.1128/aac.01684-21 .

Barbachyn MR, Hutchinson DK, Brickner SJ, Cynamon MH, Kilburn JO, Klemens SP, et al. Identification of a novel oxazolidinone (U-100480) with potent antimycobacterial activity. J Med Chem. 1996;39:680–5. https://doi.org/10.1021/jm950956y .

Cynamon MH, Klemens SP, Sharpe CA, Chase S. Activities of several novel oxazolidinones against Mycobacterium tuberculosis in a murine model. Antimicrob Agents Chemother. 1999;43:1189–91. https://doi.org/10.1128/AAC.43.5.1189 .

Alffenaar JWC, van der Laan T, Simons S, van der Werf TS, van de Kasteele PJ, de Neeling H, et al. Susceptibility of clinical Mycobacterium tuberculosis isolates to a potentially less toxic derivate of linezolid, PNU-100480. Antimicrob Agents Chemother. 2011;55:1287–9. https://doi.org/10.1128/AAC.01297-10 .

Williams KN, Stover CK, Zhu T, Tasneen R, Tyagi S, Grosset JH, et al. Promising antituberculosis activity of the oxazolidinone PNU-100480 relative to that of linezolid in a murine model. Antimicrob Agents Chemother. 2009;53:1314–9. https://doi.org/10.1128/AAC.01182-08 .

Wallis RS, Dawson R, Friedrich SO, Venter A, Paige D, Zhu T, et al. Mycobactericidal activity of sutezolid (PNU-100480) in sputum (EBA) and blood (WBA) of patients with pulmonary tuberculosis. PLoS One. 2014;9:e94462. https://doi.org/10.1371/journal.pone.0094462 .

TB Alliance. Our Pipeline. Sutezolid. 2023 [Accessed 14 April 2023]. Available from: https://www.tballiance.org/portfolio/trial/12018 .

Pethe K, Bifani P, Jang J, Kang S, Park S, Ahn S, et al. Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nat Med. 2013;19:1157–60. https://doi.org/10.1038/nm.3262 .

Kang S, Kim RY, Seo MJ, Lee S, Kim YM, Seo M, et al. Lead optimization of a novel series of imidazo[1,2- a ]pyridine amides leading to a clinical candidate (Q203) as a multi- and extensively-drug-resistant anti-tuberculosis agent. J Med Chem. 2014;57:5293–305. https://doi.org/10.1038/nm.3262 .

Kim J, Choi J, Kang H, Ahn J, Hutchings J, Niekerk CV, et al. Safety, tolerability, pharmacokinetics, and metabolism of telacebec (Q203) for the treatment of tuberculosis: a randomized, placebo-controlled, multiple ascending dose phase 1B trial. Antimicrob Agents Chemother. 2023;67:e01123–22. https://doi.org/10.1128/aac.01123-22 .

de Jager VR, Dawson R, van Niekerk C, Hutchings J, Kim J, Vanker N, et al. Telacebec (Q203), a new antituberculosis agent. N Engl J Med. 2020;382:1280–1. https://doi.org/10.1056/NEJMc1913327 .

Lee BS, Pethe K. Telacebec: an investigational antibacterial for the treatment of tuberculosis (TB). Expert Opin Invest Drugs. 2022;31:139–44. https://doi.org/10.1080/13543784.2022.2030309 .

Moraski GC, Seeger N, Miller PA, Oliver AG, Boshoff HI, Cho S, et al. Arrival of imidazo[2,1- b ]thiazole-5-carboxamides: Potent anti-tuberculosis agents that target QcrB. ACS Infect Dis. 2016;2:393–8. https://doi.org/10.1021/acsinfecdis.5b00154 .

Lee BS, Kalia NP, Jin XEF, Hasenoehrl EJ, Berney M, Pethe K. Inhibitors of energy metabolism interfere with antibiotic-induced death in mycobacteria. J Biol Chem. 2019;294:1936–43. https://doi.org/10.1074/jbc.RA118.005732 .

Thomas SS, Kalia NP, Ruf M-T, Pluschke G, Pethe K. Toward a single-dose cure for Buruli ulcer. Antimicrob Agents Chemother. 2020;64:e00727–20. https://doi.org/10.1128/AAC.00727-20 .

Komm O, Almeida DV, Converse PJ, Omansen TF, Nuermberger EL. Impact of dose, duration, and immune status on efficacy of ultrashort telacebec regimens in mouse models of Buruli ulcer. Antimicrob Agents Chemother. 2021;65:e01418–21. https://doi.org/10.1128/AAC.01418-21 .

Brown-Elliott BA, Rubio A, Wallace RJ Jr. In vitro susceptibility testing of a novel benzimidazole, SPR719, against nontuberculous mycobacteria. Antimicrob Agents Chemother. 2018;62:e01503–18. https://doi.org/10.1128/aac.01503-18 .

Pidot SJ, Porter JL, Lister T, Stinear TP. In vitro activity of SPR719 against Mycobacterium ulcerans , Mycobacterium marinum and Mycobacterium chimaera . PLoS Negl Trop Dis. 2021;15:e0009636. https://doi.org/10.1371/journal.pntd.0009636 .

Aragaw WW, Cotroneo N, Stokes S, Pucci M, Critchley I, Gengenbacher M, et al. In vitro resistance against DNA gyrase inhibitor SPR719 in Mycobacterium avium and Mycobacterium abscessus . Microbiol Spectr. 2022;10:e01321–21. https://doi.org/10.1128/spectrum.01321-21 .

Talley AK, Thurston A, Moore G, Gupta VK, Satterfield M, Manyak E, et al. First-in-human evaluation of the safety, tolerability, and pharmacokinetics of SPR720, a novel oral bacterial DNA gyrase (GyrB) inhibitor for mycobacterial infections. Antimicrob Agents Chemother. 2021;65:e01208–21. https://doi.org/10.1128/AAC.01208-21 .

O’Dowd H, Shannon DE, Chandupatla KR, Dixit V, Engtrakul JJ, Ye Z, et al. Discovery and characterization of a water-soluble prodrug of a dual inhibitor of bacterial DNA gyrase and topoisomerase IV. ACS Med Chem Lett. 2015;6:822–6. https://doi.org/10.1021/acsmedchemlett.5b00196 .

Locher CP, Jones SM, Hanzelka BL, Perola E, Shoen CM, Cynamon MH, et al. A novel inhibitor of gyrase B is a potent drug candidate for treatment of tuberculosis and nontuberculosis mycobacterial infections. Antimicrob Agents Chemother. 2015;59:1455–65. https://doi.org/10.1128/AAC.04347-14 .

Grillot A-L, Tiran AL, Shannon D, Krueger E, Liao Y, O’Dowd H, et al. Second-generation antibacterial benzimidazole ureas: Discovery of a preclinical candidate with reduced metabolic liability. J Med Chem. 2014;57:8792–816. https://doi.org/10.1021/jm500563g .

Durcik M, Tomašič T, Zidar N, Zega A, Kikelj D, Mašič LP, et al. ATP-competitive DNA gyrase and topoisomerase IV inhibitors as antibacterial agents. Expert Opin Ther Pat. 2019;29:171–80. https://doi.org/10.1080/13543776.2019.1575362 .

Makarov V, Manina G, Mikusova K, Möllmann U, Ryabova O, Saint-Joanis B, et al. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science. 2009;324:801–4. https://doi.org/10.1126/science.1171583 .

Batt SM, Jabeen T, Bhowruth V, Quill L, Lund PA, Eggeling L, et al. Structural basis of inhibition of Mycobacterium tuberculosis DprE1 by benzothiazinone inhibitors. Proc Natl Acad Sci USA. 2012;109:11354–9. https://doi.org/10.1073/pnas.1205735109 .

Trefzer C, Škovierová H, Buroni S, Bobovská A, Nenci S, Molteni E, et al. Benzothiazinones are suicide inhibitors of mycobacterial decaprenylphosphoryl-β-D-ribofuranose 2′-oxidase DprE1. J Am Chem Soc. 2012;134:912–5. https://doi.org/10.1021/ja211042r .

Neres J, Pojer F, Molteni E, Chiarelli LR, Dhar N, Boy-Röttger S, et al. Structural basis for benzothiazinone-mediated killing of Mycobacterium tuberculosis . Sci Transl Med. 2012;4:150ra21. https://doi.org/10.1126/scitranslmed.3004395 .

Shi J, Lu J, Wen SA, Zong Z, Huo F, Luo J, et al. In vitro activity of PBTZ169 against multiple Mycobacterium species. Antimicrob Agents Chemother. 2018;62:e01314–18. https://doi.org/10.1128/aac.01314-18 .

Kloss F, Krchnak V, Krchnakova A, Schieferdecker S, Dreisbach J, Krone V, et al. In vivo dearomatization of the potent antituberculosis agent BTZ043 via Meisenheimer complex formation. Angew Chem, Int Ed. 2017;56:2187–91. https://doi.org/10.1002/anie.201609737 .

Liu R, Krchnak V, Brown SN, Miller MJ. Deuteration of BTZ043 extends the lifetime of Meisenheimer intermediates to the antituberculosis nitroso oxidation state. ACS Med Chem Lett. 2019;10:1462–6. https://doi.org/10.1021/acsmedchemlett.9b00308 .

Hariguchi N, Chen X, Hayashi Y, Kawano Y, Fujiwara M, Matsuba M, et al. OPC-167832, a novel carbostyril derivative with potent antituberculosis activity as a DprE1 inhibitor. Antimicrob Agents Chemother. 2020;64:e02020–19. https://doi.org/10.1128/AAC.02020-19 .

OPC-167832 (Working Group on New TB Drugs) [Accessed 4 January 2023]. Available from: https://www.newtbdrugs.org/pipeline/compound/opc-167832 .

Li X, Hernandez V, Rock FL, Choi W, Mak YSL, Mohan M, et al. Discovery of a potent and specific M. tuberculosis leucyl-tRNA synthetase inhibitor: ( S )-3-(aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[ c ][1,2]oxaborol-1(3 H )-ol (GSK656). J Med Chem. 2017;60:8011–26. https://doi.org/10.1021/acs.jmedchem.7b00631 .

Tenero D, Derimanov G, Carlton A, Tonkyn J, Davies M, Cozens S, et al. First-time-in-human study and prediction of early bactericidal activity for GSK3036656, a potent leucyl-tRNA synthetase inhibitor for tuberculosis treatment. Antimicrob Agents Chemother. 2019;63:e00240–19. https://doi.org/10.1128/aac.00240-19 .

Shirude PS, Shandil R, Sadler C, Naik M, Hosagrahara V, Hameed S, et al. Azaindoles: noncovalent DprE1 inhibitors from scaffold morphing efforts, kill Mycobacterium tuberculosis and are efficacious in vivo. J Med Chem. 2013;56:9701–8. https://doi.org/10.1021/jm401382v .

Shirude PS, Shandil RK, Manjunatha MR, Sadler C, Panda M, Panduga V, et al. Lead optimization of 1,4-azaindoles as antimycobacterial agents. J Med Chem. 2014;57:5728–37. https://doi.org/10.1021/jm500571f .

Chatterji M, Shandil R, Manjunatha MR, Solapure S, Ramachandran V, Kumar N, et al. 1,4-Azaindole, a potential drug candidate for treatment of tuberculosis. Antimicrob Agents Chemother. 2014;58:5325–31. https://doi.org/10.1128/AAC.03233-14 .

Huang Z, Luo W, Xu D, Guo F, Yang M, Zhu Y, et al. Discovery and preclinical profile of sudapyridine (WX-081), a novel anti-tuberculosis agent. Bioorg Med Chem Lett. 2022;71:128824 https://doi.org/10.1016/j.bmcl.2022.128824 .

Yao R, Wang B, Fu L, Li L, You K, Li Y-G, et al. Sudapyridine (WX-081), a novel compound against Mycobacterium tuberculosis . Microbiol Spectr. 2022;10:e02477–21. https://doi.org/10.1128/spectrum.02477-21 .

Zhu R, Shang Y, Chen S, Xiao H, Ren R, Wang F, et al. In vitro activity of the sudapyridine (WX-081) against non-tuberculous mycobacteria isolated in Beijing, China. Microbiol Spectr. 2022;10:e01372–22. https://doi.org/10.1128/spectrum.01372-22 .

Zhang D, Lu Y, Liu K, Liu B, Wang J, Zhang G, et al. Identification of less lipophilic riminophenazine derivatives for the treatment of drug-resistant tuberculosis. J Med Chem. 2012;55:8409–17. https://doi.org/10.1021/jm300828h .

Dey T, Brigden G, Cox H, Shubber Z, Cooke G, Ford N. Outcomes of clofazimine for the treatment of drug-resistant tuberculosis: a systematic review and meta-analysis. J Antimicrob Chemother. 2012;68:284–93. https://doi.org/10.1093/jac/dks389 .

Mirnejad R, Asadi A, Khoshnood S, Mirzaei H, Heidary M, Fattorini L, et al. Clofazimine: a useful antibiotic for drug-resistant tuberculosis. Biomed Pharmacother. 2018;105:1353–9. https://doi.org/10.1016/j.biopha.2018.06.023 .

Xu J, Wang B, Fu L, Zhu H, Guo S, Huang H, et al. In vitro and in vivo activities of the riminophenazine TBI-166 against Mycobacterium tuberculosis . Antimicrob Agents Chemother. 2019;63:e02155–18. https://doi.org/10.1128/aac.02155-18 .

Zhang Y, Zhu H, Fu L, Wang B, Guo S, Chen X, et al. Identifying regimens containing TBI-166, a new drug candidate against Mycobacterium tuberculosis in vitro and in vivo. Antimicrob Agents Chemother. 2019;63:e02496–18. https://doi.org/10.1128/aac.02496-18 .

Zhu H, Fu L, Wang B, Chen X, Zhao J, Huang H, et al. Activity of clofazimine and TBI-166 against Mycobacterium tuberculosis in different administration intervals in mouse tuberculosis models. Antimicrob Agents Chemother. 2021;65:e02164–20. https://doi.org/10.1128/AAC.02164-20 .

Ding Y, Zhu H, Fu L, Zhang W, Wang B, Guo S, et al. Superior efficacy of a TBI-166, bedaquiline, and pyrazinamide combination regimen in a murine model of tuberculosis. Antimicrob Agents Chemother. 2022;66:e00658–22. https://doi.org/10.1128/aac.00658-22 .

Lv C, Li Y, Wei Y, Wang J, Yu H, Gao F, et al. Research progress on small molecular inhibitors of the Type 3 secretion system. Molecules. 2022;27:8348. https://doi.org/10.3390/molecules27238348 .

Nesterenko LN, Zigangirova NA, Zayakin ES, Luyksaar SI, Kobets NV, Balunets DV, et al. A small-molecule compound belonging to a class of 2,4-disubstituted 1,3,4-thiadiazine-5-ones suppresses Salmonella infection in vivo. J Antibiot. 2016;69:422–7. https://doi.org/10.1038/ja.2015.131 .

Zigangirova NA, Zayakin ES, Kapotina LN, Kost EA, Didenko LV, Davydova DY, et al. Development of chlamydial type III secretion system inhibitors for suppression of acute and chronic forms of chlamydial infection. Acta Nat. 2012;4:87–97.

Sheremet AB, Zigangirova NA, Zayakin ES, Luyksaar SI, Kapotina LN, Nesterenko LN, et al. Small molecule inhibitor of type three secretion system belonging to a class 2,4-disubstituted-4H-[1,3,4]-thiadiazine-5-ones improves survival and decreases bacterial loads in an airway Pseudomonas aeruginosa infection in mice. Biomed Res Int. 2018:5810767. https://doi.org/10.1155/2018/5810767 .

Zigangirova NA, Nesterenko LN, Sheremet AB, Soloveva AV, Luyksaar SI, Zayakin ES, et al. Fluorothiazinon, a small-molecular inhibitor of T3SS, suppresses Salmonella oral infection in mice. J Antibiot. 2021;74:244–54. https://doi.org/10.1038/s41429-020-00396-w .

Subbian S, Koo M-S, Tsenova L, Khetani V, Zeldis JB, Fallows D, et al. Pharmacologic inhibition of host phosphodiesterase-4 improves isoniazid-mediated clearance of Mycobacterium tuberculosis . Front Immunol. 2016;7:238. https://doi.org/10.3389/fimmu.2016.00238 .

Subbian S, Tsenova L, Holloway J, Peixoto B, O’Brien P, Dartois V, et al. Adjunctive phosphodiesterase-4 inhibitor therapy improves antibiotic response to pulmonary tuberculosis in a rabbit model. eBioMedicine. 2016;4:104–14. https://doi.org/10.1016/j.ebiom.2016.01.015 .

Amgen licenses AMG 634, an investigational treatment for tuberculosis and leprosy, to Medicines Development for Global Health (Press release 22 December 2020) [Accessed 4 January 2023]. Available from: https://www.medicinesdevelopment.com/news/mdgh-announces-in-licensing-of-investigational-treatment-for-tb-and-leprosy-from-amgen .

Working Group on New TB Drugs, CC-11050 [Accessed 4 January 2023]. Available from: https://www.newtbdrugs.org/pipeline/compound/cc-11050 .

Wallis RS, Ginindza S, Beattie T, Arjun N, Likoti M, Edward VA, et al. Adjunctive host-directed therapies for pulmonary tuberculosis: a prospective, open-label, phase 2, randomised controlled trial. Lancet Respir Med. 2021;9:897–908. https://doi.org/10.1016/S2213-2600(20)30448-3 .

Wallis RS, Ginindza S, Beattie T, Arjun N, Likoti M, Sebe M, et al. Lung and blood early biomarkers for host-directed tuberculosis therapies: Secondary outcome measures from a randomized controlled trial. PLoS One. 2022;17:e0252097. https://doi.org/10.1371/journal.pone.0252097 .

Zhang Y, Zhao C, Wang Q, Wang X, Chen H, Li H, et al. Evaluation of the in vitro activity of new polymyxin B analogue SPR206 against clinical MDR, colistin-resistant and tigecycline-resistant Gram-negative bacilli. J Antimicrob Chemother. 2020;75:2609–15. https://doi.org/10.1093/jac/dkaa217 .

Spero Therapeutics announces third quarter 2022 operating results and provides business update (Press release 14 November 2022) [Accessed 2 January 2023]. Available from: https://s3.amazonaws.com/b2icontent.irpass.cc/2748/rl113755.pdf .

Spero Therapeutics signs license agreement with Everest Medicines to develop, manufacture and commercialize SPR206 in Asia, with option for SPR741 rights, and initiates SPR206 Phase 1 Clinical Trial (Press release 7 January 2019) [Accessed 2 February 2023]. Available from: https://www.globenewswire.com/news-release/2019/01/07/1681644/0/en/Spero-Therapeutics-Signs-License-Agreement-with-Everest-Medicines-to-Develop-Manufacture-and-Commercialize-SPR206-in-Asia-with-Option-for-SPR741-Rights-and-Initiates-SPR206-Phase-1.html .

Lepak AJ, Wang W, Andes DR. Pharmacodynamic evaluation of MRX-8, a novel polymyxin, in the neutropenic mouse thigh and lung infection models against Gram-negative pathogens. Antimicrob Agents Chemother. 2020;64:e01517–20. https://doi.org/10.1128/AAC.01517-20 .

Duncan LR, Wang W, Sader HS. In vitro potency and spectrum of the novel polymyxin MRX-8 tested against clinical isolates of Gram-negative bacteria. Antimicrob Agents Chemother. 2022;66:e00139–22. https://doi.org/10.1128/aac.00139-22 .

Wu S, Yin D, Zhi P, Guo Y, Yang Y, Zhu D, et al. In vitro activity of MRX-8 and comparators against clinical isolated Gram-negative bacilli in China. Front Cell Infect Microbiol. 2022;12:829592. https://doi.org/10.3389/fcimb.2022.829592 .

MicuRx Pipeline [Accessed 2 January 2023]. Available from: https://www.micurx.com/pipeline .

Gordeev MF, Liu J, Wang X, Yuan Z. inventors; MicuRx Pharmaceuticals, assignee. Antimicrobial polymyxins for treatment of bacterial infections. USA patent 9771394. 2019.

Griffith D, Carmeli Y, Gehrke S, Morgan E, Dudley M, Loutit J. 217. A phase 1 study of the safety, tolerability, and pharmacokinetics of multiple doses of the lipopeptide QPX9003 in healthy adult subjects. Open Forum Infect Dis. 2022;9. https://doi.org/10.1093/ofid/ofac492.295 .

Roberts KD, Zhu Y, Azad MAK, Han M-L, Wang J, Wang L, et al. A synthetic lipopeptide targeting top-priority multidrug-resistant Gram-negative pathogens. Nat Commun. 2022;13:1625. https://doi.org/10.1038/s41467-022-29234-3 .

Roche Pipeline [Accessed 3 January 2023]. Available from: https://www.roche.com/solutions/pipeline .

Szałaj N, Benediktsdottir A, Rusin D, Karlén A, Mowbray SL, Więckowska A. Bacterial type I signal peptidase inhibitors - Optimized hits from nature. Eur J Med Chem. 2022;238:114490. https://doi.org/10.1016/j.ejmech.2022.114490 .

Smith PA, Koehler MFT, Girgis HS, Yan D, Chen Y, Chen Y, et al. Optimized arylomycins are a new class of Gram-negative antibiotics. Nature. 2018;561:189–94. https://doi.org/10.1038/s41586-018-0483-6 .

Tan YX, Peters DS, Walsh SI, Holcomb M, Santos-Martins D, Forli S, et al. Initial analysis of the arylomycin D antibiotics. J Nat Prod. 2020;83:2112–21. https://doi.org/10.1021/acs.jnatprod.9b01174 .

Pfaller MA, Li L, Liu Q, Zhang J, Huband MD, Lindley JM, et al. In vitro activity of a novel aminomethylcycline antibacterial (KBP-7072), a third-generation tetracycline, against clinical isolates with molecularly characterized tetracycline resistance mechanisms. JAC Antimicrob Resist. 2021;3:dlab177. https://doi.org/10.1093/jacamr/dlab177 .

Huband MD, Thompson JD, Gurung ND, Liu Q, Li L, Zhang J, et al. Activity of the novel aminomethylcycline KBP-7072 and comparators against 1057 geographically diverse recent clinical isolates from the SENTRY Surveillance Program, 2019. Antimicrob Agents Chemother. 2022;66:e01397–21. https://doi.org/10.1128/AAC.01397-21 .

Han R, Ding L, Yang Y, Guo Y, Yin D, Wu S, et al. In vitro activity of KBP-7072 against 536 Acinetobacter baumannii complex isolates collected in China. Microbiol Spectr. 2022;10:e01471–21. https://doi.org/10.1128/spectrum.01471-21 .

Kaminishi T, Schedlbauer A, Ochoa-Lizarralde B, Astigarraga ED, Çapuni R, Yang F et al. The third-generation tetracycline KBP-7072 exploits and reveals a new potential of the primary tetracycline binding pocket. bioRxiv. 2018:508218. https://doi.org/10.1101/508218 .

Juhas M, Widlake E, Teo J, Huseby DL, Tyrrell JM, Polikanov YS, et al. In vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii . J Antimicrob Chemother. 2019;74:944–52. https://doi.org/10.1093/jac/dky546 .

Gysin M, Hon PY, Tan P, Sengduangphachanh A, Simmalavong M, Hinfonthong P, et al. Apramycin susceptibility of multidrug-resistant Gram-negative blood culture isolates in five countries in Southeast Asia. Int J Antimicrob Agents. 2022;60:106659. https://doi.org/10.1016/j.ijantimicag.2022.106659 .

Tian E, Muhammad I, Hu W, Wu Z, Li R, Lu X, et al. Tentative epidemiologic cut-off value and resistant characteristic detection of apramycin against Escherichia coli from chickens. FEMS Microbiol Lett. 2019;366:fnz196. https://doi.org/10.1093/femsle/fnz196 .

Committee for veterinary medicinal products. Apramycin. Summary Report (1) 1997 [Accessed 24 January 2023]. Available from: https://www.ema.europa.eu/en/documents/mrl-report/apramycin-summary-report-1-committee-veterinary-medicinal-products_en.pdf .

Thompson RQ, Presti EA. Nebramycin, a new broad-spectrum antibiotic complex. III. Isolation and chemical-physical properties. Antimicrob Agents Chemother. 1968:332–40.

O’Connor S, Lam LKT, Jones ND, Chaney MO. Apramycin, a unique aminocyclitol antibiotic. J Org Chem. 1976;41:2087–92. https://doi.org/10.1021/jo00874a003 .

Huang DB, Brothers KM, Mandell JB, Taguchi M, Alexander PG, Parker DM, et al. Engineered peptide PLG0206 overcomes limitations of a challenging antimicrobial drug class. PLoS One. 2022;17:e0274815. https://doi.org/10.1371/journal.pone.0274815 .

Heinrich F, Salyapongse A, Kumagai A, Dupuy FG, Shukla K, Penk A, et al. Synergistic biophysical techniques reveal structural mechanisms of engineered cationic antimicrobial peptides in lipid model membranes. Chem Eur J. 2020;26:6247–56. https://doi.org/10.1002/chem.202000212 .

Huang D, Dobbins D, Ghahramani P, Friedland I, Steckbeck J. A phase 1 study of the safety, tolerability, and pharmacokinetics of single ascending doses of a first-in-human engineered cationic peptide, PLG0206, intravenously administered in healthy subjects. Antimicrob Agents Chemother. 2022;66:e01441–21. https://doi.org/10.1128/AAC.01441-21 .

Deslouches B, Steckbeck JD, Craigo JK, Doi Y, Burns JL, Montelaro RC. Engineered cationic antimicrobial peptides to overcome multidrug resistance by ESKAPE pathogens. Antimicrob Agents Chemother. 2015;59:1329–33. https://doi.org/10.1128/AAC.03937-14 .

Huang D, Pachuda N, Sauer JM, Dobbins D, Steckbeck J. The engineered antibiotic peptide PLG0206 eliminates biofilms and is a potential treatment for periprosthetic joint infections. Antibiotics. 2022;11:41. https://doi.org/10.3390/antibiotics11010041 .

Zhao L, Huang Y, Gao S, Cui Y, He D, Wang L, et al. Comparison on effect of hydrophobicity on the antibacterial and antifungal activities of α-helical antimicrobial peptides. Sci China Chem. 2013;56:1307–14. https://doi.org/10.1007/s11426-013-4884-y .

Mai X-T, Huang J, Tan J, Huang Y, Chen Y. Effects and mechanisms of the secondary structure on the antimicrobial activity and specificity of antimicrobial peptides. J Pept Sci. 2015;21:561–8. https://doi.org/10.1002/psc.2767 .

Hao X, Yan Q, Zhao J, Wang W, Huang Y, Chen Y. TAT modification of alpha-helical anticancer peptides to improve specificity and efficacy. PLoS One. 2015;10:e0138911. https://doi.org/10.1371/journal.pone.0138911 .

Andolina G, Bencze L-C, Zerbe K, Müller M, Steinmann J, Kocherla H, et al. A peptidomimetic antibiotic interacts with the periplasmic domain of LptD from Pseudomonas aeruginosa . ACS Chem Biol. 2018;13:666–75. https://doi.org/10.1021/acschembio.7b00822 .

Srinivas N, Jetter P, Ueberbacher BJ, Werneburg M, Zerbe K, Steinmann J, et al. Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa . Science. 2010;327:1010–3. https://doi.org/10.1126/science.1182749 .

Botos I, Noinaj N, Buchanan SK. Insertion of proteins and lipopolysaccharide into the bacterial outer membrane. Philos Trans R Soc Lond B Biol Sci. 2017;372:20160224. https://doi.org/10.1098/rstb.2016.0224 .

Spexis Pipeline. Inhaled Murepavadin [Accessed 2 January 2023]. Available from: https://spexisbio.com/pol7080/ .

Polyphor temporarily halts enrollment in the phase III studies of murepavadin for the treatment of patients with nosocomial pneumonia (Press release 9 May 2019) [Accessed 2 February 2023]. Available from: https://spexisbio.com/news/corporate-news-details/?newsid=1775911 .

TAXIS Pharmaceuticals Pipeline [Accessed 2 January 2023]. Available from: https://www.taxispharma.com/research-development/our-pipeline/ .

Carro L. Recent progress in the development of small-molecule FtsZ inhibitors as chemical tools for the development of novel antibiotics. Antibiotics. 2019;8:217 https://doi.org/10.3390/antibiotics8040217 .

Elsen NL, Lu J, Parthasarathy G, Reid JC, Sharma S, Soisson SM, et al. Mechanism of action of the cell-division inhibitor PC190723: Modulation of FtsZ assembly cooperativity. J Am Chem Soc. 2012;134:12342–5. https://doi.org/10.1021/ja303564a .

Haydon DJ, Stokes NR, Ure R, Galbraith G, Bennett JM, Brown DR, et al. An inhibitor of FtsZ with potent and selective anti-staphylococcal activity. Science. 2008;321:1673–5. https://doi.org/10.1126/science.1159961 .

Haydon DJ, Bennett JM, Brown D, Collins I, Galbraith G, Lancett P, et al. Creating an antibacterial with in vivo efficacy: synthesis and characterization of potent inhibitors of the bacterial cell division protein FtsZ with improved pharmaceutical properties. J Med Chem. 2010;53:3927–36. https://doi.org/10.1021/jm9016366 .

Stokes NR, Baker N, Bennett JM, Berry J, Collins I, Czaplewski LG, et al. An improved small-molecule inhibitor of FtsZ with superior in vitro potency, drug-like properties, and in vivo efficacy. Antimicrob Agents Chemother. 2013;57:317–25. https://doi.org/10.1128/aac.01580-12 .

Kaul M, Mark L, Zhang Y, Parhi AK, Lyu YL, Pawlak J, et al. TXA709, an FtsZ-targeting benzamide prodrug with improved pharmacokinetics and enhanced in vivo efficacy against methicillin-resistant Staphylococcus aureus . Antimicrob Agents Chemother. 2015;59:4845–55. https://doi.org/10.1128/AAC.00708-15 .

Lepak AJ, Parhi A, Madison M, Marchillo K, VanHecker J, Andes DR. In vivo pharmacodynamic evaluation of an FtsZ inhibitor, TXA-709, and its active metabolite, TXA-707, in a murine neutropenic thigh infection mode. Antimicrob Agents Chemother. 2015;59:6568–74. https://doi.org/10.1128/aac.01464-15 .

Mattei P. Discovery of RG6006, a tethered macrocyclic peptide targeting Acinetobacter baumannii (15th Winter Conference on Medicinal & Bioorganic Chemistry, Steamboat Springs Resort, CO, USA) 2022 [Accessed 23 February 2023]. Available from: https://mbcfconference.com/wp-content/uploads/2022/04/Patrizio-Mattei-2023-MBCF-abstract.pdf .

Bleicher K, Cheang D, Giorgio PD, Hu T, Mattei P, Schmitz P, et al. inventors; Hoffmann La Roche Inc, assignee. Peptide macrocycles against Acinetobacter baumannii . USA patent 11505573. 2022.

Desai J, S S, Kumar S, Sharma R. Novel bacterial topoisomerase inhibitors (NBTIs)—a comprehensive review. Eur J Med Chem Rep. 2021;3:100017. https://doi.org/10.1016/j.ejmcr.2021.100017 .

Mohamed SHP, Bharatham N, Katagihallimath N, Sharma S, Nandishaiah R, Ramachandran V et al. inventors; Bugworks Research Inc, assignee. Heterocyclic compounds useful as anti-bacterial agents and method for production thereof. USA patent 10912780. 2021.

Hameed S, Sharma S, Nandishaiah R, Katagihallimath N, Bharatham N, Shanbhag A, et al. BWC0977, a novel dual target topoisomerase inhibitor: antimicrobial potency, spectrum and mechanism of action (ECCMID 2019, Amsterdam, Netherlands, Poster #P1844). 2019 [Accessed 23 February 2023]. Available from: https://bugworksresearch.com/wp-content/uploads/2021/11/e-20190415_ECCMID_P1844.pdf .

Raveendran S, Thomas T, Sharma M, Rajagopal S, Prabhumurthy S, Nagaraj S, et al. In vitro activity of BWC0977 (a novel bacterial topoisomerase inhibitor) and comparators against recent clinical Enterobacteriaceae and non-fermenter Isolates from two hospitals in Bengaluru, India (ECCMID 2019, Amsterdam, Netherlands, Poster #P1845). 2019 [Accessed 23 February 2023]. Available from: https://bugworksresearch.com/wp-content/uploads/2021/11/d-20190415_ECCMID_P1845.pdf .

Wiederhold NP, McElmeel M, Patterson TF, Slayden RA, Cummings JE, Ramachandran V, et al. In vitro activity of BWC0977, a novel bacterial topoisomerase inhibitor, against molecularly characterized Enterobacteriaceae & non-fermenter isolates of the CDC collection and key biodefense pathogens (ECCMID 2019, Amsterdam, Netherlands, Poster #1845). 2019 [Accessed 23 February 2023]. Available from: https://bugworksresearch.com/wp-content/uploads/2021/11/c-20190415_ECCMID_P1846.pdf .

Makarov V, Mikušová K. Development of macozinone for TB treatment: an update. Appl Sci. 2020;10:2269. https://doi.org/10.3390/app10072269 .

Koryakova A, Shcherbakova V, Riabova O, Kazaishvili Y, Bolgarin R, Makarov V. Antituberculosis macozinone extended-release tablets to enhance bioavailability: a pilot pharmacokinetic study in beagle dogs. Microbiol Spectr. 2023;11:e02327–22. https://doi.org/10.1128/spectrum.02327-22 .

Working Group on New TB Drugs, TBI-223 [Accessed 2 January 2023]. Available from: https://www.newtbdrugs.org/pipeline/compound/tbi-223 .

Gordon O, Dikeman DA, Ortines RV, Wang Y, Youn C, Mumtaz M, et al. The novel oxazolidinone TBI-223 is effective in three preclinical mouse models of methicillin-resistant Staphylococcus aureus infection. Microbiol Spectr. 2022;10:e02451–21. https://doi.org/10.1128/spectrum.02451-21 .

Almeida D, Converse PJ, Li S-Y, Upton AM, Fotouhi N, Nuermberger EL. Comparative efficacy of the novel diarylquinoline TBAJ-876 and bedaquiline against a resistant Rv0678 mutant in a mouse model of tuberculosis. Antimicrob Agents Chemother. 2021;65:e01412–21. https://doi.org/10.1128/AAC.01412-21 .

Sarathy JP, Ganapathy US, Zimmerman MD, Dartois V, Gengenbacher M, Dick T. TBAJ-876, a 3,5-dialkoxypyridine analogue of bedaquiline, is active against Mycobacterium abscessus . Antimicrob Agents Chemother. 2020;64:e02404–19. https://doi.org/10.1128/AAC.02404-19 .

Sutherland HS, Tong AST, Choi PJ, Blaser A, Conole D, Franzblau SG, et al. 3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel. Bioorg Med Chem. 2019;27:1292–307. https://doi.org/10.1016/j.bmc.2019.02.026 .

Choi PJ, Conole D, Sutherland HS, Blaser A, Tong AST, Cooper CB, et al. Synthetic studies to help elucidate the metabolism of the preclinical candidate TBAJ-876—a less toxic and more potent analogue of bedaquiline. Molecules. 2020;25:1423. https://doi.org/10.3390/molecules25061423 .

Sarathy JP, Ragunathan P, Shin J, Cooper CB, Upton AM, Grüber G, et al. TBAJ-876 retains bedaquiline’s activity against subunits c and ε of Mycobacterium tuberculosis F-ATP synthase. Antimicrob Agents Chemother. 2019;63:e01191–19. https://doi.org/10.1128/AAC.01191-19 .

Sarathy JP, Ragunathan P, Cooper CB, Upton AM, Grüber G, Dick T. TBAJ-876 displays bedaquiline-like mycobactericidal potency without retaining the parental drug’s uncoupler activity. Antimicrob Agents Chemother. 2020;64:e01540–19. https://doi.org/10.1128/AAC.01540-19 .

Krah A, Grüber G, Bond PJ. Binding properties of the anti-TB drugs bedaquiline and TBAJ-876 to a mycobacterial F-ATP synthase. Curr Res Struct Biol. 2022;4:278–84. https://doi.org/10.1016/j.crstbi.2022.09.001 .

Xu J, Converse PJ, Upton AM, Mdluli K, Fotouhi N, Nuermberger EL. Comparative efficacy of the novel diarylquinoline TBAJ-587 and bedaquiline against a resistant Rv0678 mutant in a mouse model of tuberculosis. Antimicrob Agents Chemother. 2021;65:e02418–20. https://doi.org/10.1128/AAC.02418-20 .

Working Group on New TB Drugs, GSK-286 [Accessed 3 January 2023]. Available from: https://www.newtbdrugs.org/pipeline/compound/gsk-286 .

Nuermberger EL, Martínez-Martínez MS, Sanz O, Urones B, Esquivias J, Soni H, et al. GSK2556286 is a novel antitubercular drug candidate effective in vivo with the potential to shorten tuberculosis treatment. Antimicrob Agents Chemother. 2022;66:e00132–22. https://doi.org/10.1128/aac.00132-22 .

Mehta V, Khanppnavar B, Schuster D, Kantarci I, Vercellino I, Kosturanova A, et al. Structure of Mycobacterium tuberculosis Cya, an evolutionary ancestor of the mammalian membrane adenylyl cyclases. eLife. 2022;11:e77032. https://doi.org/10.7554/eLife.77032 .

Brown KL, Wilburn KM, Montague CR, Grigg Jason C, Sanz O, Pérez-Herrán E, et al. Cyclic AMP-mediated inhibition of cholesterol catabolism in Mycobacterium tuberculosis by the novel drug candidate GSK2556286. Antimicrob Agents Chemother. 2023;67:e01294–22. https://doi.org/10.1128/aac.01294-22 .

VanderVen BC, Fahey RJ, Lee W, Liu Y, Abramovitch RB, Memmott C, et al. Novel inhibitors of cholesterol degradation in Mycobacterium tuberculosis reveal how the bacterium’s metabolism is constrained by the intracellular environment. PLoS Pathog. 2015;11:e1004679. https://doi.org/10.1371/journal.ppat.1004679 .

Working Group on New TB Drugs, BVL-GSK098 [Accessed 4 January 2023]. Available from: https://www.newtbdrugs.org/pipeline/compound/bvl-gsk098 .

Blondiaux N, Moune M, Desroses M, Frita R, Flipo M, Mathys V, et al. Reversion of antibiotic resistance in Mycobacterium tuberculosis by spiroisoxazoline SMARt-420. Science. 2017;355:1206–11. https://doi.org/10.1126/science.aag1006 .

Guieu B, Jourdan J-P, Dreneau A, Willand N, Rochais C, Dallemagne P. Desirable drug–drug interactions or when a matter of concern becomes a renewed therapeutic strategy. Drug Disco Today. 2021;26:315–28. https://doi.org/10.1016/j.drudis.2020.11.026 .

CARB-X funds GSK to develop a new drug for urinary tract infections (UTI) caused by Escherichia coli bacteria (Press release 22 September 2020) [Accessed 4 January 2023]. Available from: https://carb-x.org/carb-x-news/carb-x-announces-funding-for-gsk-to-develop-a-new-drug-for-urinary-tract-infections-uti-caused-by-escherichia-coli-bacteria/ .

Ronald A. The etiology of urinary tract infection: traditional and emerging pathogens. Am J Med. 2002;113:14–9. https://doi.org/10.1016/S0002-9343(02)01055-0 .

Foroogh N, Rezvan M, Ahmad K, Mahmood S. Structural and functional characterization of the FimH adhesin of uropathogenic Escherichia coli and its novel applications. Micro Pathog. 2021;161:105288. https://doi.org/10.1016/j.micpath.2021.105288 .

Mydock-McGrane LK, Hannan TJ, Janetka JW. Rational design strategies for FimH antagonists: new drugs on the horizon for urinary tract infection and Crohn’s disease. Expert Opin Drug Disco. 2017;12:711–31. https://doi.org/10.1080/17460441.2017.1331216 .

Kalas V, Hibbing ME, Maddirala AR, Chugani R, Pinkner JS, Mydock-McGrane LK, et al. Structure-based discovery of glycomimetic FmlH ligands as inhibitors of bacterial adhesion during urinary tract infection. Proc Natl Acad Sci USA. 2018;115:E2819–E28. https://doi.org/10.1073/pnas.1720140115 .

Maddirala AR, Klein R, Pinkner JS, Kalas V, Hultgren SJ, Janetka JW. Biphenyl Gal and GalNAc FmlH lectin antagonists of uropathogenic E. coli (UPEC): Optimization through iterative rational drug design. J Med Chem. 2019;62:467–79. https://doi.org/10.1021/acs.jmedchem.8b01561 .

Bishop MJ, Stewart EL, Widdowson KL, Janetka JW, McGrane LK. inventors; GlaxoSmithKline Intellectual Property Development Ltd, Fimbrion Therapeutics Inc, assignee. C-mannoside compounds useful for the treatment of urinary tract infections. USA patent 11111262. 2021.

Liu C-I, Liu GY, Song Y, Yin F, Hensler ME, Jeng W-Y, et al. A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence. Science. 2008;319:1391–4. https://doi.org/10.1126/science.1153018 .

Elmesseri RA, Saleh SE, Elsherif HM, Yahia IS, Aboshanab KM. Staphyloxanthin as a potential novel target for deciphering promising anti- Staphylococcus aureus agents. Antibiotics. 2022;11:298. https://doi.org/10.3390/antibiotics11030298 .

Kao YTR, Gao P, Li X, Liu M. inventors; Versitech Ltd, assignee. Compounds affecting pigment production and methods for treatment of bacterial diseases. USA patent 11052078. 2021.

Gao P, Davies J, Kao RYT. Dehydrosqualene desaturase as a novel target for anti-virulence therapy against Staphylococcus aureus . mBio. 2017;8:e01224–17. https://doi.org/10.1128/mBio.01224-17 .

Barnes MD, Kumar V, Bethel CR, Moussa SH, O’Donnell J, Rutter JD, et al. Targeting multidrug-resistant Acinetobacter spp.: sulbactam and the diazabicyclooctenone β-lactamase inhibitor ETX2514 as a novel therapeutic agent. mBio. 2019;10:e00159–19. https://doi.org/10.1128/mBio.00159-19 .

McLeod SM, Shapiro AB, Moussa SH, Johnstone M, McLaughlin RE, de Jonge BLM, et al. Frequency and mechanism of spontaneous resistance to sulbactam combined with the novel β-lactamase inhibitor ETX2514 in clinical isolates of Acinetobacter baumannii . Antimicrob Agents Chemother. 2018;62:e01576–17. https://doi.org/10.1128/aac.01576-17 .

Granata G, Taglietti F, Schiavone F, Petrosillo N. Durlobactam in the treatment of multidrug-resistant Acinetobacter baumannii infections: a systematic review. J Clin Med. 2022;11:3258. https://doi.org/10.3390/jcm11123258 .

Innoviva announces FDA acceptance and priority review of New Drug Application for Sulbactam-Durlobactam (SUL-DUR) (Press release 30 November 2022) [Accessed 7 January 2023]. Available from: https://investor.inva.com/news-releases/news-release-details/innoviva-announces-fda-acceptance-and-priority-review-new-drug .

Durand-Réville TF, Guler S, Comita-Prevoir J, Chen B, Bifulco N, Huynh H, et al. ETX2514 is a broad-spectrum β-lactamase inhibitor for the treatment of drug-resistant Gram-negative bacteria including Acinetobacter baumannii . Nat Microbiol. 2017;2:17104. https://doi.org/10.1038/nmicrobiol.2017.104 .

Shapiro AB, Gao N, Jahić H, Carter NM, Chen A, Miller AA. Reversibility of covalent, broad-spectrum serine β-lactamase inhibition by the diazabicyclooctenone ETX2514. ACS Infect Dis. 2017;3:833–44. https://doi.org/10.1021/acsinfecdis.7b00113 .

O’Donnell J, Preston RA, Mamikonyan G, Stone E, Isaacs R. Pharmacokinetics, safety, and tolerability of intravenous durlobactam and sulbactam in subjects with renal impairment and healthy matched control subjects. Antimicrob Agents Chemother. 2019;63:e00794–19. https://doi.org/10.1128/AAC.00794-19 .

Liu B, Trout REL, Chu G-H, McGarry D, Jackson RW, Hamrick J, et al. Discovery of taniborbactam (VNRX-5133): A broad-spectrum serine- and metallo-β-lactamase inhibitor for carbapenem-resistant bacterial infections. J Med Chem. 2020;63:2789–801. https://doi.org/10.1021/acs.jmedchem.9b01518 .

Venatorx Pharmaceuticals announces positive results for Phase 3 clinical trial (CERTAIN-1) of cefepime-taniborbactam for treatment of cUTI (Press release 10 March 2022) [Accessed 7 January 2023]. Available from: https://www.venatorx.com/press-releases/venatorx-pharmaceuticals-announces-positive-results-for-phase-3-clinical-trial-certain-1-of-cefepime-taniborbactam-for-treatment-of-cuti/ .

Venatorx Pharmaceuticals presents data on investigational cefepime-taniborbactam at IDWeek 2022 (Press release 20 October 2022) [Accessed 7 January 2023]. Available from: https://www.venatorx.com/press-releases/venatorx-pharmaceuticals-presents-data-on-investigational-cefepime-taniborbactam-at-idweek-2022/ .

Meletiadis J, Paranos P, Georgiou P-C, Vourli S, Antonopoulou S, Michelaki A, et al. In vitro comparative activity of the new beta-lactamase inhibitor taniborbactam with cefepime or meropenem against Klebsiella pneumoniae and cefepime against Pseudomonas aeruginosa metallo-beta-lactamase-producing clinical isolates. Int J Antimicrob Agents. 2021;58:106440 https://doi.org/10.1016/j.ijantimicag.2021.106440 .

Roach EJ, Uehara T, Daigle DM, Six DA, Khursigara CM. The next-generation β-lactamase inhibitor taniborbactam restores the morphological effects of cefepime in KPC-producing Escherichia coli . Microbiol Spectr. 2021;9:e00918–21. https://doi.org/10.1128/Spectrum.00918-21 .

Hernández-García M, García-Castillo M, Ruiz-Garbajosa P, Bou G, Siller-Ruiz M, Pitart C, et al. In vitro activity of cefepime-taniborbactam against carbapenemase-producing Enterobacterales and Pseudomonas aeruginosa isolates recovered in Spain. Antimicrob Agents Chemother. 2022;66:e02161–21. https://doi.org/10.1128/aac.02161-21 .

Lence E, González-Bello C. Bicyclic boronate β-lactamase inhibitors: the present hope against deadly bacterial pathogens. Adv Ther. 2021;4:2000246. https://doi.org/10.1002/adtp.202000246 .

Krajnc A, Brem J, Hinchliffe P, Calvopina K, Panduwawala T, Lang PA, et al. Bicyclic boronate VNRX-5133 inhibits metallo- and serine-β-lactamases. J Med Chem. 2019;62:8544–56. https://doi.org/10.1021/acs.jmedchem.9b00911 .

Mameli M, Vezzelli A, Verze’ S, Biondi S, Motta P, Greco A, et al. Liquid chromatography–tandem mass spectrometry for the simultaneous quantitation of enmetazobactam and cefepime in human plasma. J Pharm Biomed Anal. 2019;174:655–62. https://doi.org/10.1016/j.jpba.2019.06.041 .

Crandon JL, Nicolau DP. In vivo activities of simulated human doses of cefepime and cefepime-AAI101 against multidrug-resistant Gram-negative Enterobacteriaceae. Antimicrob Agents Chemother. 2015;59:2688–94. https://doi.org/10.1128/AAC.00033-15 .

Crandon JL, Nicolau DP. In vitro activity of cefepime/AAI101 and comparators against cefepime non-susceptible Enterobacteriaceae. Pathogens. 2015;4:620–5. https://doi.org/10.3390/pathogens4030620 .

Kaye KS, Belley A, Barth P, Lahlou O, Knechtle P, Motta P, et al. Effect of cefepime/enmetazobactam vs piperacillin/tazobactam on clinical cure and microbiological eradication in patients with complicated urinary tract infection or acute pyelonephritis: A randomized clinical trial. JAMA. 2022;328:1304–14. https://doi.org/10.1001/jama.2022.17034 .

Papp-Wallace KM, Nguyen NQ, Jacobs MR, Bethel CR, Barnes MD, Kumar V, et al. Strategic approaches to overcome resistance against Gram-negative pathogens using β-lactamase inhibitors and β-lactam enhancers: Activity of three novel diazabicyclooctanes WCK 5153, zidebactam (WCK 5107), and WCK 4234. J Med Chem. 2018;61:4067–86. https://doi.org/10.1021/acs.jmedchem.8b00091 .

Moya B, Barcelo IM, Bhagwat S, Patel M, Bou G, Papp-Wallace KM, et al. Potent β-lactam enhancer activity of zidebactam and WCK 5153 against Acinetobacter baumannii , including carbapenemase-producing clinical isolates. Antimicrob Agents Chemother. 2017;61:e01238–17. https://doi.org/10.1128/aac.01238-17 .

Sader HS, Mendes RE, Duncan LR, Carvalhaes CG, Castanheria M. Antimicrobial activity of cefepime/zidebactam (WCK 5222), a β-lactam/β-lactam enhancer combination, against clinical isolates of Gram-negative bacteria collected worldwide (2018–19). J Antimicrob Chemother. 2022;77:2642–9. https://doi.org/10.1093/jac/dkac233 .

Guo Y, Han R, Jiang B, Ding L, Yang F, Zheng B, et al. In vitro activity of new β-lactam–β-lactamase inhibitor combinations and comparators against clinical isolates of Gram-negative bacilli: Results from the China Antimicrobial Surveillance Network (CHINET) in 2019. Microbiol Spectr. 2022;10:e01854–22. https://doi.org/10.1128/spectrum.01854-22 .

Mushtaq S, Garello P, Vickers A, Woodford N, Livermore DM. Activity of ertapenem/zidebactam (WCK 6777) against problem Enterobacterales . J Antimicrob Chemother. 2022;77:2772–8. https://doi.org/10.1093/jac/dkac280 .

Morinaka A, Tsutsumi Y, Yamada M, Suzuki K, Watanabe T, Abe T, et al. OP0595, a new diazabicyclooctane: mode of action as a serine β-lactamase inhibitor, antibiotic and β-lactam ‘enhancer’. J Antimicrob Chemother. 2015;70:2779–86. https://doi.org/10.1093/jac/dkv166 .

Asempa TE, Motos A, Abdelraouf K, Bissantz C, Zampaloni C, Nicolau DP. Efficacy of Human-simulated epithelial lining fluid exposure of meropenem-nacubactam combination against class a serine β-lactamase-producing Enterobacteriaceae in the neutropenic murine lung infection model. Antimicrob Agents Chemother. 2019;63:e02382–18. https://doi.org/10.1128/aac.02382-18 .

Livermore DM, Warner M, Mushtaq S, Woodford N. Interactions of OP0595, a novel triple-action diazabicyclooctane, with β-lactams against OP0595-resistant Enterobacteriaceae mutants. Antimicrob Agents Chemother. 2016;60:554–60. https://doi.org/10.1128/AAC.02184-15 .

Garde D. Roche inks a $750M antibiotics deal as it re-embraces the field (Fierce Biotech 13 Jan 2015) [Accessed 2 February 2023]. Available from: http://www.fiercebiotech.com/story/roche-inks-750m-antibiotics-deal-it-re-embraces-field/2015-01-13 .

Garde D. Roche, Meiji and Fedora join forces to tackle increasing bacterial resistance to antibiotics [Accessed 2 February 2023]. Available from: https://www.fiercebiotech.com/biotech/roche-meiji-and-fedora-join-forces-to-tackle-increasing-bacterial-resistance-to-antibiotics .

Meiji Seika Pipeline, As of November 8, 2022 [Accessed 8 January 2023]. Available from: https://www.meiji.com/global/pharmaceuticals/pipeline.html .

Fedora Pharmaceuticals Website, Our Story [Accessed 8 Januray 2023]. Available from: https://www.fedorapharma.com/about-us .

Hecker SJ, Reddy KR, Lomovskaya O, Griffith DC, Rubio-Aparicio D, Nelson K, et al. Discovery of cyclic boronic acid QPX7728, an ultrabroad-spectrum inhibitor of serine and metallo-β-lactamases. J Med Chem. 2020;63:7491–507. https://doi.org/10.1021/acs.jmedchem.9b01976 .

Lomovskaya O, Tsivkovski R, Sun D, Reddy R, Totrov M, Hecker S, et al. QPX7728, an ultra-broad-spectrum β-lactamase inhibitor for intravenous and oral therapy: Overview of biochemical and microbiological characteristics. Front Microbiol. 2021;12. https://doi.org/10.3389/fmicb.2021.697180 .

Lomovskaya O, Rubio-Aparicio D, Tsivkovski R, Loutit J, Dudley M. The ultrabroad-spectrum beta-lactamase inhibitor QPX7728 restores the potency of multiple oral beta-lactam antibiotics against beta-lactamase-producing strains of resistant Enterobacterales . Antimicrob Agents Chemother. 2022;66:e02168–21. https://doi.org/10.1128/aac.02168-21 .

Sun D, Tsivkovski R, Pogliano J, Tsunemoto H, Nelson K, Rubio-Aparicio D, et al. Intrinsic antibacterial activity of xeruborbactam in vitro: assessing spectrum and mode of action. Antimicrob Agents Chemother. 2022;66:e00879–22. https://doi.org/10.1128/aac.00879-22 .

Reddy KR, Parkinson J, Sabet M, Tarazi Z, Boyer SH, Lomovskaya O, et al. Selection of QPX7831, an orally bioavailable prodrug of boronic acid β-lactamase inhibitor QPX7728. J Med Chem. 2021;64:17523–9. https://doi.org/10.1021/acs.jmedchem.1c01722 .

Durand-Réville TF, Comita-Prevoir J, Zhang J, Wu X, May-Dracka TL, Romero JAC, et al. Discovery of an orally available diazabicyclooctane inhibitor (ETX0282) of class A, C, and D serine β-lactamases. J Med Chem. 2020;63:12511–25. https://doi.org/10.1021/acs.jmedchem.0c00579 .

Miller AA, Shapiro AB, McLeod SM, Carter NM, Moussa SH, Tommasi R, et al. In Vitro characterization of ETX1317, a broad-spectrum β-lactamase inhibitor that restores and enhances β-lactam activity against multi-drug-resistant Enterobacteriales , including carbapenem-resistant strains. ACS Infect Dis. 2020;6:1389–97. https://doi.org/10.1021/acsinfecdis.0c00020 .

Trout RE, Zulli A, Mesaros E, Jackson RW, Boyd S, Liu B, et al. Discovery of VNRX-7145 (VNRX-5236 etzadroxil): an orally bioavailable β-lactamase inhibitor for Enterobacterales expressing Ambler class A, C, and D enzymes. J Med Chem. 2021;64:10155–66. https://doi.org/10.1021/acs.jmedchem.1c00437 .

Karlowsky JA, Hackel MA, Sahm DF. In vitro activity of ceftibuten/VNRX-5236 against urinary tract infection isolates of antimicrobial-resistant Enterobacterales . Antimicrob Agents Chemother. 2022;66:e01304–21. https://doi.org/10.1128/AAC.01304-21 .

Chatwin CL, Hamrick JC, Trout REL, Myers CL, Cusick SM, Weiss WJ, et al. Microbiological characterization of VNRX-5236, a broad-spectrum β-lactamase inhibitor for rescue of the orally bioavailable cephalosporin ceftibuten as a carbapenem-sparing agent against strains of Enterobacterales expressing extended-spectrum β-lactamases and serine carbapenemases. Antimicrob Agents Chemother. 2021;65:e00552–21. https://doi.org/10.1128/AAC.00552-21 .

Karlowsky JA, Wisek MG, Hackel MA, Pevear DC, Moeck G, Sahm DF. Ceftibuten-ledaborbactam activity against multidrug-resistant and extended-spectrum-β-lactamase-positive clinical isolates of Enterobacterales from a 2018–2020 global surveillance collection. Antimicrob Agents Chemother. 2022;66:e00934–22. https://doi.org/10.1128/aac.00934-22 .

Wu Y, Huang S, Chen X, Hu Y, Liu X. inventors; Suzhou Sinovent Pharmaceuticals, assignee. β-Lactamase inhibitor and use thereof. USA patent 11078202. 2021.

Heo Y-A. Imipenem/cilastatin/relebactam: a review in Gram-negative bacterial infections. Drugs. 2021;81:377–88. https://doi.org/10.1007/s40265-021-01471-8 .

Dietl B, Martínez LM, Calbo E, Garau J. Update on the role of ceftazidime-avibactam in the management of carbapenemase-producing Enterobacterales. Future Microbiol. 2020;15:473–84. https://doi.org/10.2217/fmb-2020-0012 .

Gordon EM, Duncton MAJ, Gallop MA. Orally absorbed derivatives of the β-lactamase inhibitor avibactam. Design of novel prodrugs of sulfate containing drugs. J Med Chem. 2018;61:10340–4. https://doi.org/10.1021/acs.jmedchem.8b01389 .

Biospace. Arixa Pharmaceuticals announces acquisition by Pfizer’s hospital business 2020 [Accessed 7 January 2023]. Available from: https://www.biospace.com/article/releases/arixa-pharmaceuticals-announces-acquisition-by-pfizer-s-hospital-business/ .

Kohanski MA, Dwyer DJ, Collins JJ. How antibiotics kill bacteria: from targets to networks. Nat Rev Microbiol. 2010;8:423–35. https://doi.org/10.1038/nrmicro2333 .

Bisacchi GS, Manchester JI. A new-class antibacterial—almost. Lessons in drug discovery and development: a critical analysis of more than 50 years of effort toward ATPase inhibitors of DNA gyrase and topoisomerase IV. ACS Infect Dis. 2015;1:4–41. https://doi.org/10.1021/id500013t .

Zhou S, Wang W, Zhou X, Zhang Y, Lai Y, Tang Y, et al. Structure of Mycobacterium tuberculosis cytochrome bcc in complex with Q203 and TB47, two anti-TB drug candidates. eLife. 2021;10:e69418. https://doi.org/10.7554/eLife.69418 .

Hards K, Adolph C, Harold LK, McNeil MB, Cheung C-Y, Jinich A, et al. Two for the price of one: attacking the energetic-metabolic hub of mycobacteria to produce new chemotherapeutic agents. Prog Biophys Mol Biol. 2019;152:35–44. https://doi.org/10.1016/j.pbiomolbio.2019.11.003 .

IQVIA Institute. Global Oncology Trends 2022 2022 [Accessed 28 February 2023]. Available from: https://www.iqvia.com/insights/the-iqvia-institute/reports/global-oncology-trends-2022 .

World Health Organization. COVID-19 vaccine tracker and landscape 2023 [Accessed 28 February 2023]. Available from: https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines .

USA FDA. Limited Population Pathway for Antibacterial and Antifungal Drugs – the LPAD Pathway 2020 [Accessed 23 February 2023]. Available from: https://www.fda.gov/drugs/development-resources/limited-population-pathway-antibacterial-and-antifungal-drugs-lpad-pathway .

Noviello S, Huang DB, Corey GR. Iclaprim: a differentiated option for the treatment of skin and skin structure infections. Expert Rev Anti Infect Ther. 2018;16:793–803. https://doi.org/10.1080/14787210.2018.1536545 .

Protopopova M, Hanrahan C, Nikonenko B, Samala R, Chen P, Gearhart J, et al. Identification of a new antitubercular drug candidate, SQ109, from a combinatorial library of 1,2-ethylenediamines. J Antimicrob Chemother. 2005;56:968–74. https://doi.org/10.1093/jac/dki319 .

Sacksteder KA, Protopopova M, Barry CE, Andries K, Nacy CA. Discovery and development of SQ109: a new antitubercular drug with a novel mechanism of action. Future Microbiol. 2012;7:823–37. https://doi.org/10.2217/fmb.12.56 .

Infectex announces positive phase 2b-3 clinical trial results of SQ109 for the treatment of multidrug-resistant pulmonary tuberculosis (Press Release 21 March 2017) [Accessed 2 February 2023]. Available from: https://www.newtbdrugs.org/sites/default/files/downloads/Infectex%20Press%20Release.2017.0321.pdf .

Borisov SE, Bogorodskaya EM, Volchenkov GV, Kulchavenya EV, Maryandyshev AO, Skornyakov SN, et al. Efficiency and safety of chemotherapy regimen with SQ109 in those suffering from multiple drug resistant tuberculosis. Tuberc Lung Dis. 2018;96:6–18. https://doi.org/10.21292/2075-1230-2018-96-3-6-18 .

Sattar A, Thommes P, Payne L, Warn P, Vickers RJ. SMT19969 for Clostridium difficile infection (CDI): In vivo efficacy compared with fidaxomicin and vancomycin in the hamster model of CDI. J Antimicrob Chemother. 2015;70:1757–62. https://doi.org/10.1093/jac/dkv005 .

Bassères E, Endres BT, Khaleduzzaman M, Miraftabi F, Alam MJ, Vickers RJ, et al. Impact on toxin production and cell morphology in Clostridium difficile by ridinilazole (SMT19969), a novel treatment for C. difficile infection. J Antimicrob Chemother. 2016;71:1245–51. https://doi.org/10.1093/jac/dkv498 .

Collins DA, Riley TV. Ridinilazole: a novel, narrow‐spectrum antimicrobial agent targeting Clostridium ( Clostridioides ) difficile . Lett Appl Microbiol. 2022;75:526–36. https://doi.org/10.1111/lam.13664 .

Summit Therapeutics Presents Ri-CoDIFy Trial Results for Microbiome-Sparing Ridinilazole at IDWeek 2022 (Press release 20 October 2022) [Accessed 2 February 2023]. Available from: https://www.smmttx.com/app/uploads/2022/10/2022_PR_1020_ID-Week-2022-Results-_-FINAL.pdf .

Reck F, Bermingham A, Blais J, Capka V, Cariaga T, Casarez A, et al. Optimization of novel monobactams with activity against carbapenem-resistant Enterobacteriaceae – identification of LYS228. Bioorg Med Chem Lett. 2018;28:748–55. https://doi.org/10.1016/j.bmcl.2018.01.006 .

Blais J, Lopez S, Li C, Ruzin A, Ranjitkar S, Dean CR, et al. In vitro activity of LYS228, a novel monobactam antibiotic, against multidrug-resistant Enterobacteriaceae. Antimicrob Agents Chemother. 2018;62:e00552–18. https://doi.org/10.1128/AAC.00552-18 .

Oka D, Changkwanyeun R, Yamaguchi T, Nakajima C, Suzuki Y, Matsumoto M. In vitro antibacterial activity of OPS-2071 against Gram-positive and Gram-negative enteropathogenic bacteria. J Antimicrob Chemother. 2022;77:3248–55. https://doi.org/10.1093/jac/dkac308 .

Oka D, Yamaya N, Kuno T, Asakawa Y, Shiragiku T, Chen L, et al. In vitro and in vivo antibacterial activities of a novel quinolone compound, OPS-2071, against Clostridioides difficile . Antimicrob Agents Chemother. 2021;65:e01170–20. https://doi.org/10.1128/AAC.01170-20 .

Falagas ME, Skalidis T, Vardakas KZ, Voulgaris GL, Papanikolaou G, Legakis N. Activity of TP-6076 against carbapenem-resistant Acinetobacter baumannii isolates collected from inpatients in Greek hospitals. Int J Antimicrob Agents. 2018;52:269–71. https://doi.org/10.1016/j.ijantimicag.2018.03.009 .

Morgan CE, Zhang Z, Bonomo RA, Yu EW. An analysis of the novel fluorocycline TP-6076 bound to both the ribosome and multidrug efflux pump AdeJ from Acinetobacter baumannii . mBio. 2022;13:e03732–21. https://doi.org/10.1128/mbio.03732-21 .

Article   CAS   PubMed Central   Google Scholar  

Grossman TH, Fyfe C, O’Brien W, Hackel M, Minyard MB, Waites KB, et al. Fluorocycline TP-271 is potent against complicated community-acquired bacterial pneumonia pathogens. mSphere. 2017;2:e00004–17. https://doi.org/10.1128/mSphere.00004-17 .

Grossman TH, Anderson MS, Drabek L, Gooldy M, Heine HS, Henning LN, et al. The fluorocycline TP-271 is efficacious in models of aerosolized Bacillus anthracis infection in BALB/c mice and cynomolgus macaques. Antimicrob Agents Chemother. 2017;61:e01103–17. https://doi.org/10.1128/aac.01103-17 .

Grossman TH, Anderson MS, Christ D, Gooldy M, Henning LN, Heine HS, et al. The fluorocycline TP-271 is efficacious in models of aerosolized Francisella tularensis SCHU S4 Infection in BALB/c mice and cynomolgus macaques. Antimicrob Agents Chemother. 2017;61:e00448–17. https://doi.org/10.1128/aac.00448-17 .

Stainton SM, Abdelraouf K, Utley L, Pucci MJ, Lister T, Nicolau DP. Assessment of the in vivo activity of SPR741 in combination with azithromycin against multidrug-resistant Enterobacteriaceae isolates in the neutropenic murine thigh infection model. Antimicrob Agents Chemother. 2018;62:e00239–18. https://doi.org/10.1128/aac.00239-18 .

Corbett D, Wise A, Langley T, Skinner K, Trimby E, Birchall S, et al. Potentiation of antibiotic activity by a novel cationic peptide: Potency and spectrum of activity of SPR741. Antimicrob Agents Chemother. 2017;61:e00200–17. https://doi.org/10.1128/aac.00200-17 .

Halasohoris SA, Scarff JM, Pysz LM, Lembirik S, Lemmon MM, Biek D, et al. In vitro and in vivo activity of GT-1, a novel siderophore cephalosporin, and GT-055, a broad-spectrum β-lactamase inhibitor, against biothreat and ESKAPE pathogens. J Antibiot. 2021;74:884–92. https://doi.org/10.1038/s41429-021-00472-9 .

Nguyen LP, Park CS, Pinto NA, Lee H, Seo HS, Vu TN et al. In vitro activity of a novel siderophore-cephalosporin LCB10-0200 (GT-1), and LCB10-0200/avibactam, against carbapenem-resistant Escherichia coli , Klebsiella pneumoniae , Acinetobacter baumannii , and Pseudomonas aeruginosa strains at a tertiary hospital in Korea. Pharmaceuticals. 2021;14. https://doi.org/10.3390/ph14040370 .

Weiss A, Delavenne E, Matias C, Lagler H, Simon D, Li P, et al. Topical niclosamide (ATx201) reduces Staphylococcus aureus colonization and increases Shannon diversity of the skin microbiome in atopic dermatitis patients in a randomized, double-blind, placebo-controlled phase 2 trial. Clin Transl Med. 2022;12:e790. https://doi.org/10.1002/ctm2.790 .

Peck M, Rothenberg ME, Deng R, Lewin-Koh N, She G, Kamath AV, et al. A phase 1, randomized, single-ascending-dose study to investigate the safety, tolerability, and pharmacokinetics of DSTA4637S, an anti- Staphylococcus aureus thiomab antibody-antibiotic conjugate, in healthy volunteers. Antimicrob Agents Chemother. 2019;63:e02588–18. https://doi.org/10.1128/aac.02588-18 .

Deng R, Zhou C, Li D, Cai H, Sukumaran S, Carrasco-Triguero M, et al. Preclinical and translational pharmacokinetics of a novel THIOMAB™ antibody-antibiotic conjugate against Staphylococcus aureus . mAbs. 2019;11:1162–74. https://doi.org/10.1080/19420862.2019.1627152 .

Download references

Acknowledgements

The authors would like to thank the researchers, organizations, and companies who responded to enquiries.

Open Access funding enabled and organized by CAUL and its Member Institutions.

Author information

Authors and affiliations.

Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, 4072, Australia

Mark S. Butler, Ian R. Henderson, Robert J. Capon & Mark A. T. Blaskovich

You can also search for this author in PubMed   Google Scholar

Corresponding authors

Correspondence to Mark S. Butler or Mark A. T. Blaskovich .

Ethics declarations

Conflict of interest.

MATB has conducted antibiotic research that was funded by Botanix Pharmaceuticals and has received funding from CARB-X. MATB is an inventor of patents describing novel antibiotics.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The original online version of this article was revised: The authors of the above article have noticed that prodrug contezolid acefosamil (3) was incorrectly stated as being approved rather than contezolid (4). This has been corrected throughout the review. The changes are below: In the sentence in the third paragraph of the introduction beginning “The new antibacterial drugs approved since the previous 2019 review…”, “contezolid acefosamil (3)” should have been “contezolid (4)”. In Table 1, the drug name “contezolid acefosamil (3) (prodrug)” should have been “contezolid (4)”, without “(prodrug)”. In the sentence beginning “Since the 2019 review…”, in paragraph 2 of the section “Antibacterial drugs launched from January 2013 to December 2022”, “contezolid acefosamil (3)” should have been “contezolid (4)”. In the fourth paragraph of the section “Antibacterial drugs launched from January 2013 to December 2022”, several changes have been made. In the first sentence, “Contezolid acefosamil (3)” has been changed to “Contezolid (4)”, “(Youxitai, MRX-4, po)” has been changed to “(Youxitai, MRX-1, IV)”, and the word “prodrug” has been removed. In the third sentence, “(MRX-1)” has been removed, and “3” has been changed to “contezolid acefosamil (3)”. In the fourth sentence, “The prodrug” has been changed to “The prodrug 3”. In the “Conclusion and outlook” section, in the sentence beginning “There were only two new small molecule antibacterial drugs…”, “the oxazolidinone contezolid acefosamil (3)” should have read “the oxazolidinone contezolid (4)”. In addition, there was also an error in the “New antibacterial pharmacophore analysis” section where it was stated that gepotidacin (10) inhibited GyrB and not GyrA. The mode of action of gepotidacin (10) is correctly described elsewhere in the review. GyrB has been corrected to GyrA. The original article has been corrected.

Supplementary information

Supplementary information, rights and permissions.

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ .

Reprints and permissions

About this article

Cite this article.

Butler, M.S., Henderson, I.R., Capon, R.J. et al. Antibiotics in the clinical pipeline as of December 2022. J Antibiot 76 , 431–473 (2023). https://doi.org/10.1038/s41429-023-00629-8

Download citation

Received : 02 March 2023

Revised : 20 April 2023

Accepted : 25 April 2023

Published : 08 June 2023

Issue Date : August 2023

DOI : https://doi.org/10.1038/s41429-023-00629-8

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

This article is cited by

Ecological and evolutionary mechanisms driving within-patient emergence of antimicrobial resistance.

• Matthew J. Shepherd
• Michael A. Brockhurst

Nature Reviews Microbiology (2024)

The twin challenges of longevity and climate change in controlling antimicrobial resistance

• Maryam Shafaati
• Mohammadreza Salehi
• Maryam Zare

The Journal of Antibiotics (2024)

Endophytes: a uniquely tailored source of potential antibiotic adjuvants

• Ashaimaa Y. Moussa

Archives of Microbiology (2024)

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies