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Global health perspectives on antibacterial drug discovery and the preclinical pipeline

Nature Reviews Microbiology volume 23, pages 474–490 (2025)Cite this article

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Abstract

Antibacterial resistance is a global challenge that requires a coordinated international response. The current clinical pipeline largely consists of derivatives of established antibiotic classes, whereas the discovery and preclinical pipeline is diverse and innovative including new direct-acting agents with no cross-resistance with existing antibiotics. These novel compounds target pathways such as lipoprotein synthesis, lipopolysaccharide biosynthesis and transport, outer membrane assembly, peptidoglycan biosynthesis, fatty acid biosynthesis and isoprenoid biosynthesis. If these agents can be developed into safe, effective and affordable drugs, they could address a broad range of infections worldwide, benefiting large patient populations without geographical limitations. However, strategies such as indirect-acting or pathogen-specific treatments are likely to benefit small patient groups, primarily in high-income countries that have advanced health-care systems and diagnostic infrastructure. Although encouraging, the discovery and preclinical pipeline remains insufficiently robust to offset the high attrition rates typical of early-stage drug innovation and to meet global health needs.

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Fig. 1: Number of new derivatives of old antibiotic classes.
Fig. 2: Global health considerations for antibacterial drug discovery strategies.
Fig. 3: Criteria to inform a global health-relevant preclinical development pipeline.
Fig. 4: Biological targets and pathways targeted by traditional agents in late discovery and preclinical programmes.

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References

  1. Coque, T. M., Cantón, R., Pérez-Cobas, A. E., Fernández-de-Bobadilla, M. D. & Baquero, F. Antimicrobial resistance in the Global Health Network: known unknowns and challenges for efficient responses in the 21st century. Microorganisms 11, 1050 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Hernando-Amado, S., Coque, T. M., Baquero, F. & Martínez, J. L. Antibiotic resistance: moving from individual health norms to social norms in One Health and Global Health. Front. Microbiol. 11, 1914 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Okeke, I. N. et al. The scope of the antimicrobial resistance challenge. Lancet 403, 2426–2438 (2024).

    Article  CAS  PubMed  Google Scholar 

  4. Murray, C. J. L. et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 399, 629–655 (2022).

    Article  CAS  Google Scholar 

  5. Zhou, N. et al. Global antimicrobial resistance: a system-wide comprehensive investigation using the Global One Health Index. Infect. Dis. Poverty 11, 92 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Naghavi, M. et al. Global burden of bacterial antimicrobial resistance 1990–2021: a systematic analysis with forecasts to 2050. Lancet 404, 1199–1226 (2024).

    Article  Google Scholar 

  7. Brown, D. R., Henderson, H. I., Ruegsegger, L., Moody, J. & van Duin, D. Socioeconomic disparities in the prevalence of multidrug resistance in Enterobacterales. Infect. Control Hosp. Epidemiol. 44, 2068–2070 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Alividza, V. et al. Investigating the impact of poverty on colonization and infection with drug-resistant organisms in humans: a systematic review. Infect. Dis. Poverty 7, 76 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Pallett, S. J. C. et al. The contribution of human conflict to the development of antimicrobial resistance. Commun. Med. 3, 153 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Li, W. et al. Association between antibiotic resistance and increasing ambient temperature in China: an ecological study with nationwide panel data. Lancet Reg. Health West. Pac. 30, 100628 (2023).

    PubMed  Google Scholar 

  11. Muloi, D. M. et al. Exploiting genomics for antimicrobial resistance surveillance at One Health interfaces. Lancet Microbe 4, e1056–e1062 (2023).

    Article  PubMed  Google Scholar 

  12. Burnham, J. P. Climate change and antibiotic resistance: a deadly combination. Ther. Adv. Infect. Dis. 8, 204993612199137 (2021).

    Google Scholar 

  13. Laxminarayan, R. et al. Expanding antibiotic, vaccine, and diagnostics development and access to tackle antimicrobial resistance. Lancet 403, 2534–2550 (2024).

    Article  PubMed  Google Scholar 

  14. Payne, D. J., Gwynn, M. N., Holmes, D. J. & Pompliano, D. L. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat. Rev. Drug Discov. 6, 29–40 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Tommasi, R., Brown, D. G., Walkup, G. K., Manchester, J. I. & Miller, A. A. ESKAPEing the labyrinth of antibacterial discovery. Nat. Rev. Drug Discov. 14, 529–542 (2015).

    Article  CAS  PubMed  Google Scholar 

  16. Tommasi, R., Iyer, R. & Miller, A. A. Antibacterial drug discovery: some assembly required. ACS Infect. Dis. 4, 686–695 (2018).

    Article  CAS  PubMed  Google Scholar 

  17. Yao, J. & Rock, C. O. Bacterial fatty acid metabolism in modern antibiotic discovery. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1862, 1300–1309 (2017).

    Article  CAS  PubMed  Google Scholar 

  18. Baquero, F. et al. Allogenous selection of mutational collateral resistance: old drugs select for new resistance within antibiotic families. Front. Microbiol. 12, 757833 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Alsayed, S. S. R. & Gunosewoyo, H. Tuberculosis: pathogenesis, current treatment regimens and new drug targets. Int. J. Mol. Sci. 24, 5202 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. WHO. WHO antibacterial preclinical pipeline review. https://cdn.who.int/media/docs/default-source/global-observatory-on-health-r-d/who_preclinical_antibacterial_products_data_2023.xlsx?sfvrsn=4868221f_1 (WHO, 2024).

  21. Magiorakos, A.-P. et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin. Microbiol. Infect. 18, 268–281 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Karakonstantis, S., Rousaki, M., Vassilopoulou, L. & Kritsotakis, E. I. Global prevalence of cefiderocol non-susceptibility in Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia: a systematic review and meta-analysis. Clin. Microbiol. Infect. 30, 178–188 (2024).

    Article  CAS  PubMed  Google Scholar 

  23. Theuretzbacher, U. Evaluating the innovative potential of the global antibacterial pipeline. Clin. Microbiol. Infect., https://doi.org/10.1016/j.cmi.2023.09.024 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Iqbal, Z. et al. Recent developments to cope the antibacterial resistance via β-lactamase inhibition. Molecules 27, 3832 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Alfei, S. & Schito, A. M. β-lactam antibiotics and β-lactamase enzymes inhibitors, Part 2: our limited resources. Pharmaceuticals 15, 476 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Coleman, K. Diazabicyclooctanes (DBOs): a potent new class of non-β-lactam β-lactamase inhibitors. Curr. Opin. Microbiol. 14, 550–555 (2011).

    Article  CAS  PubMed  Google Scholar 

  27. Vázquez-Ucha, J. C., Arca-Suárez, J., Bou, G. & Beceiro, A. New carbapenemase inhibitors: clearing the way for the β-lactams. Int. J. Mol. Sci. 21, 9308 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Ranjitkar, S. et al. Identification of mutations in the mrdA gene encoding PBP2 that reduce carbapenem and diazabicyclooctane susceptibility of Escherichia coli clinical isolates with mutations in ftsI (PBP3) and which carry bla NDM-1. mSphere 4, 00074-19 (2019).

    Article  Google Scholar 

  29. Durand-Reville, T. F. et al. Rational design of a new antibiotic class for drug-resistant infections. Nature 597, 698–702 (2021).

    Article  CAS  PubMed  Google Scholar 

  30. Nägeli, M., Rodriguez, S., Manson, A. L., Earl, A. M. & Brennan-Krohn, T. Rapid emergence of resistance to broad-spectrum direct antimicrobial activity of avibactam. Preprint at bioRxiv https://doi.org/10.1101/2024.09.25.615047 (2024).

  31. Mojica, M. F., Rossi, M.-A., Vila, A. J. & Bonomo, R. A. The urgent need for metallo-β-lactamase inhibitors: an unattended global threat. Lancet Infect. Dis. 22, e28–e34 (2022).

    Article  CAS  PubMed  Google Scholar 

  32. Bush, K. Game changers: new β-lactamase inhibitor combinations targeting antibiotic resistance in Gram-negative bacteria. ACS Infect. Dis. 4, 84–87 (2018).

    Article  CAS  PubMed  Google Scholar 

  33. Ooi, N. et al. Restoring carbapenem efficacy: a novel carbapenem companion targeting metallo-β-lactamases in carbapenem-resistant Enterobacterales. Antimicrob. Chemother. 76, 460–466 (2021).

    Article  CAS  Google Scholar 

  34. Bertonha, A. F., Silva, C. C. L., Shirakawa, K. T., Trindade, D. M. & Dessen, A. Penicillin-binding protein (PBP) inhibitor development: a 10-year chemical perspective. Exp. Biol. Med. 248, 1657–1670 (2023).

    Article  CAS  Google Scholar 

  35. Jacobs, L. M. C., Consol, P. & Chen, Y. Drug discovery in the field of β-lactams: an academic perspective. Antibiotics 13, 59 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Uehara, T. et al. A new class of penicillin-binding protein inhibitors to address drug-resistant Neisseria gonorrhoeae. Gordon Research Conference 2024: Bacterial Cell Surfaces https://venatorx.com/wp-content/uploads/2024/08/GRC_2024_poster_NgPBPi_Uehara-final.pdf (2024).

  37. Theuretzbacher, U., Blasco, B., Duffey, M. & Piddock, L. J. V. Unrealized targets in the discovery of antibiotics for Gram-negative bacterial infections. Nat. Rev. Drug Discov. 22, 957–975 (2023).

    Article  CAS  PubMed  Google Scholar 

  38. Konovalova, A., Kahne, D. E. & Silhavy, T. J. Outer membrane biogenesis. Annu. Rev. Microbiol. 71, 539–556 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tang, X. et al. Structural basis for bacterial lipoprotein relocation by the transporter LolCDE. Nat. Struct. Mol. Biol. 28, 347–355 (2021).

    Article  CAS  PubMed  Google Scholar 

  40. Bei, W. et al. Cryo-EM structures of LolCDE reveal the molecular mechanism of bacterial lipoprotein sorting in Escherichia coli. PLoS Biol. 20, e3001823 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Breidenstein, E. B. M. et al. SMT-738: a novel small-molecule inhibitor of bacterial lipoprotein transport targeting Enterobacteriaceae. Antimicrob. Agents Chemother. 68, e0069523 (2023).

    Article  PubMed  Google Scholar 

  42. Liu, G. et al. Deep learning-guided discovery of an antibiotic targeting Acinetobacter baumannii. Nat. Chem. Biol. 19, 1342–1350 (2023).

    Article  CAS  PubMed  Google Scholar 

  43. Muñoz, K. A. et al. A Gram-negative-selective antibiotic that spares the gut microbiome. Nature 630, 429–436 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Sharma, S. et al. Mechanism of LolCDE as a molecular extruder of bacterial triacylated lipoproteins. Nat. Commun. 12, 4687 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tao, K., Narita, S., Okada, U., Murakami, S. & Tokuda, H. Dissection of an ABC transporter LolCDE function analyzed by photo-crosslinking. J. Biochem. 175, 427–437 (2024).

    Article  CAS  PubMed  Google Scholar 

  46. McLeod, S. M. et al. Small-molecule inhibitors of Gram-negative lipoprotein trafficking discovered by phenotypic screening. J. Bacteriol. 197, 1075–1082 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nickerson, N. N. et al. A novel inhibitor of the LolCDE ABC transporter essential for lipoprotein trafficking in Gram-negative bacteria. Antimicrob. Agents Chemother. 62, e02151-17 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Schuster, M. et al. Peptidomimetic antibiotics disrupt the lipopolysaccharide transport bridge of drug-resistant Enterobacteriaceae. Sci. Adv. 9, eadg3683 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Pahil, K. S. et al. A new antibiotic traps lipopolysaccharide in its intermembrane transporter. Nature 625, E27 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zampaloni, C. et al. A novel antibiotic class targeting the lipopolysaccharide transporter. Nature 623, 566–571 (2024).

    Article  Google Scholar 

  51. Seyfert, C. E. et al. New genetically engineered derivatives of antibacterial darobactins underpin their potential for antibiotic development. J. Med. Chem. 66, 16330–16341 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kaur, H. et al. The antibiotic darobactin mimics a β-strand to inhibit outer membrane insertase. Nature 593, 125–129 (2021).

    Article  CAS  PubMed  Google Scholar 

  53. Groß, S. et al. Improved broad-spectrum antibiotics against Gram-negative pathogens via darobactin biosynthetic pathway engineering. Chem. Sci. 12, 11882–11893 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Niu, Z. et al. Small molecule LpxC inhibitors against Gram-negative bacteria: advances and future perspectives. Eur. J. Med. Chem. 253, 115326 (2023).

    Article  CAS  PubMed  Google Scholar 

  55. Fujita, K. et al. TP0586532, a non-hydroxamate LpxC inhibitor, has in vitro and in vivo antibacterial activities against Enterobacteriaceae. J. Antibiot. 75, 98–107 (2022).

    Article  CAS  Google Scholar 

  56. Di Leo, R., Cuffaro, D., Rossello, A. & Nuti, E. Bacterial zinc metalloenzyme inhibitors: recent advances and future perspectives. Molecules 28, 4378 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Romano, K. P. & Hung, D. T. Targeting LPS biosynthesis and transport in Gram-negative bacteria in the era of multi-drug resistance. Biochim. Biophys. Acta Mol. Cell Res. 1870, 119407 (2023).

    Article  CAS  PubMed  Google Scholar 

  58. Zhao, J. et al. Preclinical safety and efficacy characterization of an LpxC inhibitor against Gram-negative pathogens. Sci. Transl. Med. 15, eadf5668 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Mungula, J. et al. Advanced preclinical in vitro and in vivo characterization of a novel, non-hydroxamate-based LpxC inhibitor for the intravenous and oral treatment of multidrug-resistant Enterobacterales. Gordon Research Conference New Antibacterial Discovery and Development (2024).

  60. Crunkhorn, S. LpxC inhibitor eliminates bacterial infections. Nat. Rev. Drug Discov. 22, 787 (2023).

    PubMed  Google Scholar 

  61. Krause, K. M. et al. Potent LpxC Inhibitors with in vitro activity against multidrug-resistant Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 63, e00977-19 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Karthikeyan, D., Kumar, S. & Jayaprakash, N. S. A comprehensive review of recent developments in the Gram-negative bacterial UDP-2,3-diacylglucosamine hydrolase (LpxH) enzyme. Int. J. Biol. Macromol. 267, 131327 (2024).

    Article  CAS  PubMed  Google Scholar 

  63. Wang, H. et al. Cerastecins inhibit membrane lipooligosaccharide transport in drug-resistant Acinetobacter baumannii. Nat. Microbiol. 9, 1244–1255 (2024).

    Article  CAS  PubMed  Google Scholar 

  64. Huseby, D. L. et al. Antibiotic class with potent in vivo activity targeting lipopolysaccharide synthesis in Gram-negative bacteria. Proc. Natl Acad. Sci. USA 121, e2317274121 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Zhou, P. & Hong, J. Structure- and ligand-dynamics-based design of novel antibiotics targeting lipid A enzymes LpxC and LpxH in Gram-negative bacteria. Acc. Chem. Res. 54, 1623–1634 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Alexander, M. K. et al. Disrupting Gram-negative bacterial outer membrane biosynthesis through inhibition of the lipopolysaccharide transporter MsbA. Antimicrob. Agents Chemother. 62, e01142-18 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Ho, H. et al. Structural basis for dual-mode inhibition of the ABC transporter MsbA. Nature 557, 196–201 (2018).

    Article  CAS  PubMed  Google Scholar 

  68. Kadeřábková, N., Mahmood, A. J. S., Furniss, R. C. D. & Mavridou, D. A. I. Making a chink in their armor: current and next-generation antimicrobial strategies against the bacterial cell envelope. Adv. Microb. Physiol. 83, 221–307 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Pei, S. et al. Discovery of novel tetrahydrobenzothiophene derivatives as MSBA inhibitors for antimicrobial agents. Bioorg Chem. 142, 106932 (2024).

    Article  CAS  PubMed  Google Scholar 

  70. Verma, V. A. et al. Discovery of inhibitors of the lipopolysaccharide transporter MsbA: from a screening hit to potent wild-type Gram-negative activity. J. Med. Chem. 65, 4085–4120 (2022).

    Article  CAS  PubMed  Google Scholar 

  71. Skudlarek, J. W. et al. Cerastecin inhibition of the lipooligosaccharide transporter MsbA to combat Acinetobacter baumannii: from screening impurity to in vivo efficacy. J. Med. Chem. 67, 15620–15675 (2024).

    Article  CAS  PubMed  Google Scholar 

  72. Smith, P. A. et al. Optimized arylomycins are a new class of Gram-negative antibiotics. Nature 561, 189–194 (2018).

    Article  CAS  PubMed  Google Scholar 

  73. De Rosa, M. et al. Design, synthesis and in vitro biological evaluation of oligopeptides targeting E. coli type I signal peptidase (LepB). Bioorg Med. Chem. 25, 897–911 (2017).

    Article  PubMed  Google Scholar 

  74. Huang, K.-J. et al. Deletion of a previously uncharacterized lipoprotein lirL confers resistance to an inhibitor of type II signal peptidase in Acinetobacter baumannii. Proc. Natl Acad. Sci. USA 119, e2123117119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Pantua, H. et al. Unstable mechanisms of resistance to inhibitors of Escherichia coli lipoprotein signal peptidase. mBio 11, e02018-20 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Garland, K. et al. Optimization of globomycin analogs as novel Gram-negative antibiotics. Bioorg Med. Chem. Lett. 30, 127419 (2020).

    Article  CAS  PubMed  Google Scholar 

  77. Shukla, R. et al. Teixobactin kills bacteria by a two-pronged attack on the cell envelope. Nature 608, 390–396 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Liu, Y., Liu, Y., Chan-Park, M. B. & Mu, Y. Binding modes of teixobactin to lipid II: molecular dynamics study. Sci. Rep. 7, 17197 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Parmar, A. et al. Development of teixobactin analogues containing hydrophobic, non-proteogenic amino acids that are highly potent against multidrug-resistant bacteria and biofilms. Eur. J. Med. Chem. 261, 115853 (2023).

    Article  CAS  PubMed  Google Scholar 

  80. Shukla, R. et al. An antibiotic from an uncultured bacterium binds to an immutable target. Cell 186, 4059–4073.e27 (2023).

    Article  CAS  PubMed  Google Scholar 

  81. Lin, J., Zhou, D., Steitz, T. A., Polikanov, Y. S. & Gagnon, M. G. Ribosome-targeting antibiotics: modes of action, mechanisms of resistance, and implications for drug design. Annu. Rev. Biochem. 87, 451–478 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Paternoga, H. et al. Structural conservation of antibiotic interaction with ribosomes. Nat. Struct. Mol. Biol. 30, 1380–1392 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Espejo, R. T. & Plaza, N. Multiple ribosomal RNA operons in bacteria; their concerted evolution and potential consequences on the rate of evolution of their 16S rRNA. Front. Microbiol. 9, 1232 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Pantel, L. et al. Odilorhabdins, antibacterial agents that cause miscoding by binding at a new ribosomal site. Mol. Cell 70, e7 (2018).

    Article  Google Scholar 

  85. Lanois-Nouri, A. et al. The odilorhabdin antibiotic biosynthetic cluster and acetyltransferase self-resistance locus are niche and species specific. mBio 13, e0282621 (2022).

    Article  PubMed  Google Scholar 

  86. Pantel, L. et al. Missense mutations in the CrrB protein mediate odilorhabdin derivative resistance in Klebsiella pneumoniae. Antimicrob. Agents Chemother. 65, e00139-21 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Serrano, C. M. et al. Unifying the aminohexopyranose‐ and peptidyl‐nucleoside antibiotics: implications for antibiotic design. Angew. Chem. Int. Ed. 59, 11330–11333 (2020).

    Article  CAS  Google Scholar 

  88. Vickers, A., Mushtaq, S., Woodford, N., Doumith, M. & Livermore, D. M. Activity of RX-04 pyrrolocytosine protein synthesis inhibitors against multidrug-resistant Gram-negative bacteria. Antimicrob. Agents Chemother. 62, e00689–18 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Aron, Z. D. et al. trans-Translation inhibitors bind to a novel site on the ribosome and clear Neisseria gonorrhoeae in vivo. Nat. Commun. 12, 1799 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Mitcheltree, M. J. et al. A synthetic antibiotic class overcoming bacterial multidrug resistance. Nature 599, 507–512 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Wu, K. J. Y. et al. An antibiotic preorganized for ribosomal binding overcomes antimicrobial resistance. Science 383, 721–726 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Lomeli, B. K. 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. 64, e01395-19 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Kim, S.-H., Bae, S. & Song, M. Recent development of aminoacyl-tRNA synthetase inhibitors for human diseases: a future perspective. Biomolecules 10, 1625 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. O’Dwyer, K. et al. Bacterial resistance to leucyl-tRNA synthetase inhibitor GSK2251052 develops during treatment of complicated urinary tract infections. Antimicrob. Agents Chemother. 59, 289–298 (2015).

    Article  PubMed  Google Scholar 

  95. Diacon, A. H. et al. A first-in-class leucyl-tRNA synthetase inhibitor, ganfeborole, for rifampicin-susceptible tuberculosis: a phase 2a open-label, randomized trial. Nat. Med. 30, 896–904 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Finn, P., Charlton, M., Edmund G, Jirgensons, A. & Loza, E. 2-Amino-N-(arylsulfinyl)-acetamide compounds as iInhibitors of bacterial aminoacyl-tRNA synthetase and their preparation. Patent WO2121123237A1 (2018).

  97. Knak, T. et al. Over 40 years of fosmidomycin drug research: a comprehensive review and future opportunities. Pharmaceuticals 15, 1553 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kesharwani, S. & Sundriyal, S. Non-hydroxamate inhibitors of 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR): a critical review and future perspective. Eur. J. Med. Chem. 213, 113055 (2021).

    Article  CAS  PubMed  Google Scholar 

  99. Andaloussi, M. et al. Design, synthesis, and X-ray crystallographic studies of α-aryl substituted fosmidomycin analogues as inhibitors of Mycobacterium tuberculosis 1-deoxy-d-xylulose 5-phosphate reductoisomerase. J. Med. Chem. 54, 4964–4976 (2011).

    Article  CAS  PubMed  Google Scholar 

  100. Bibens, L., Becker, J.-P., Dassonville-Klimpt, A., & Sonnet, P. Review of fatty acid biosynthesis enzyme inhibitors as promising antimicrobial drugs. Pharmaceuticals 16, 425 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Wittke, F. 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. 64, e00250-20 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Parker, E. N. et al. An iterative approach guides discovery of the FabI inhibitor fabimycin, a late-stage antibiotic candidate with in vivo efficacy against drug-resistant Gram-negative infections. ACS Cent. Sci. 8, 1145–1158 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Zorman, M., Hrast Rambaher, M., Kokot, M., Minovski, N. & Anderluh, M. The overview of development of novel bacterial topoisomerase inhibitors effective against multidrug-resistant bacteria in an academic environment: from early hits to in vivo active antibacterials. Eur. J. Pharm. Sci. 192, 106632 (2024).

    Article  CAS  PubMed  Google Scholar 

  104. Collin, F., Karkare, S. & Maxwell, A. Exploiting bacterial DNA gyrase as a drug target: current state and perspectives. Appl. Microbiol. Biotechnol. 92, 479–497 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Perry, C. R. et al. Efficacy and safety of gepotidacin as treatment of uncomplicated urogenital gonorrhea (EAGLE-1): design of a randomized, comparator-controlled, phase 3 study. Infect. Dis. Ther. 12, 2307–2320 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Hameed, P. S. et al. BWC0977, a broad-spectrum antibacterial clinical candidate to treat multidrug resistant infections. Nat. Commun. 15, 8202 (2024).

    Article  Google Scholar 

  107. Whelan, A. O. et al. In vitro activity of novel topoisomerase inhibitors against Francisella tularensis and Burkholderia pseudomallei. Antibiotics 12, 983 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Zumbrunn, C. A short history of topoisomerases at Actelion Pharmaceuticals. Chimia 76, 647 (2022).

    Article  CAS  PubMed  Google Scholar 

  109. Cumming, J. G. et al. Novel indane-containing NBTIs with potent anti-Gram-negative activity and minimal hERG inhibition. ACS Med. Chem. Lett. 14, 1791–1799 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kolarič, A. & Minovski, N. Novel bacterial topoisomerase inhibitors: challenges and perspectives in reducing hERG toxicity. Future Med. Chem. 10, 2241–2244 (2018).

    Article  PubMed  Google Scholar 

  111. Bisacchi, G. S. & Manchester, J. I. 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. 1, 4–41 (2015).

    Article  CAS  PubMed  Google Scholar 

  112. Callaway, E. ‘Groundbreaking’: first treatment targeting ‘super-gonorrhoea’ passes trial. Nature 623, 236 (2023).

    Article  CAS  PubMed  Google Scholar 

  113. Tari, L. W. et al. Tricyclic GyrB/ParE (TriBE) inhibitors: a new class of broad-spectrum dual-targeting antibacterial agents. PLoS ONE 8, e84409 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Theuretzbacher, U. & Piddock, L. J. V. Non-traditional antibacterial therapeutic options and challenges. Cell Host Microbe 26, 61–72 (2019).

    Article  CAS  PubMed  Google Scholar 

  115. Kang, S.-J., Nam, S. H. & Lee, B.-J. Engineering approaches for the development of antimicrobial peptide-based antibiotics. Antibiotics 11, 1338 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Wan, F., Torres, M. D. T., Peng, J. & de la Fuente-Nunez, C. Deep-learning-enabled antibiotic discovery through molecular de-extinction. Nat. Biomed. Eng. 8, 854–871 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Santos-Júnior, C. D. et al. Discovery of antimicrobial peptides in the global microbiome with machine learning. Cell 187, e16 (2024).

    Article  Google Scholar 

  118. Mourtada, R. et al. Design of stapled antimicrobial peptides that are stable, nontoxic and kill antibiotic-resistant bacteria in mice. Nat. Biotechnol. 37, 1186–1197 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. O’Neil, D. A. Innovation in infectious disease therapies from immunology. Drug Discov. Today 26, 2090–2094 (2021).

    Article  PubMed  Google Scholar 

  120. Murray, E., Draper, L. A., Ross, R. P. & Hill, C. The advantages and challenges of using endolysins in a clinical setting. Viruses 13, 680 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Carratalá, J. V., Arís, A., Garcia-Fruitós, E. & Ferrer-Miralles, N. Design strategies for positively charged endolysins: insights into artilysin development. Biotechnol. Adv. 69, 108250 (2023).

    Article  PubMed  Google Scholar 

  122. Jun, S. Y. et al. Pharmacokinetics and tolerance of the phage endolysin-based candidate drug SAL200 after a single intravenous administration among healthy volunteers. Antimicrob. Agents Chemother. 61, e02629-16 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Pallesen, E. M. H. et al. Endolysin inhibits skin colonization by patient-derived Staphylococcus aureus and malignant T-cell activation in cutaneous T-cell lymphoma. J. Investig. Dermatology 143, 1757–1768 (2023).

    Article  CAS  Google Scholar 

  124. Heselpoth, R. D., Euler, C. W., Schuch, R. & Fischetti, V. A. Lysocins: bioengineered antimicrobials that deliver lysins across the outer membrane of Gram-negative bacteria. Antimicrob. Agents Chemother. 63, e00342-19 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Defraine, V. et al. Efficacy of artilysin Art-175 against resistant and persistent Acinetobacter baumannii. Antimicrob. Agents Chemother. 60, 3480–3488 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Wesseling, C. M. J. & Martin, N. I. Synergy by perturbing the Gram-negative outer membrane: opening the door for Gram-positive specific antibiotics. ACS Infect. Dis. 8, 1731–1757 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Kim, S. J., Jo, J., Kim, J., Ko, K. S. & Lee, W. Polymyxin B nonapeptide potentiates the eradication of Gram-negative bacterial persisters. Microbiol. Spectr. 12, e0368723 (2024).

    Article  PubMed  Google Scholar 

  128. Vaara, M. Polymyxin derivatives that sensitize Gram-negative bacteria to other antibiotics. Molecules 24, 249 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Eckburg, P. B. et al. Safety, tolerability, pharmacokinetics, and drug interaction potential of SPR741, an intravenous potentiator, after single and multiple ascending doses and when combined with β-lactam antibiotics in healthy subjects. Antimicrob. Agents Chemother. 63, e00892-19 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Holden, E. R. et al. Mechanisms of action and synergies of a novel lipid IVA biosynthesis inhibitor. Preprint at bioRxiv https://doi.org/10.1101/2023.09.15.557861 (2023).

  131. Compagne, N. et al. Update on the discovery of efflux pump inhibitors against critical priority Gram-negative bacteria. Antibiotics 12, 180 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Zhang, Y. et al. Evaluation of a conformationally constrained indole carboxamide as a potential efflux pump inhibitor in Pseudomonas aeruginosa. Antibiotics 11, 716 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Aron, Z. & Opperman, T. J. The hydrophobic trap—the Achilles heel of RND efflux pumps. Res. Microbiol. 169, 393–400 (2018).

    Article  PubMed  Google Scholar 

  134. Li, X.-Z., Plésiat, P. & Nikaido, H. The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria. Clin. Microbiol. Rev. 28, 337–418 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Lomovskaya, O. & Bostian, K. A. Practical applications and feasibility of efflux pump inhibitors in the clinic—a vision for applied use. Biochem. Pharmacol. 71, 910–918 (2006).

    Article  CAS  PubMed  Google Scholar 

  136. Lomovskaya, O., Zgurskaya, H. I., Totrov, M. & Watkins, W. J. Waltzing transporters and ‘the dance macabre’ between humans and bacteria. Nat. Rev. Drug Discov. 6, 56–65 (2007).

    Article  CAS  PubMed  Google Scholar 

  137. Duffey, M. et al. Extending the potency and lifespan of antibiotics: inhibitors of Gram-negative bacterial efflux pumps. ACS Infect. Dis. 10, 1458–1482 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Gaurav, A., Bakht, P., Saini, M., Pandey, S. & Pathania, R. Role of bacterial efflux pumps in antibiotic resistance, virulence, and strategies to discover novel efflux pump inhibitors. Microbiology 169, 001333 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Konstantinović, J. et al. Inhibitors of the elastase LasB for the treatment of Pseudomonas aeruginosa lung infections. ACS Cent. Sci. 9, 2205–2215 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Brodie, G. & Conway, S. J. Disarming Gram-negative bacteria in the fight against antimicrobial resistance. ACS Cent. Sci. 9, 2179–2182 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Everett, M. J. & Davies, D. T. Pseudomonas aeruginosa elastase (LasB) as a therapeutic target. Drug Discov. Today 26, 2108–2123 (2021).

    Article  CAS  PubMed  Google Scholar 

  142. Ahmad-Mansour, N. et al. Staphylococcus aureus toxins: an update on their pathogenic properties and potential treatments. Toxins 13, 677 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Kim, M.-K. Staphylococcus aureus toxins: from their pathogenic roles to anti-virulence therapy using natural products. Biotechnol. Bioprocess. Eng. 24, 424–435 (2019).

    Article  CAS  Google Scholar 

  144. Jiang, J.-H., Cameron, D. R., Nethercott, C., Aires-de-Sousa, M. & Peleg, A. Y. Virulence attributes of successful methicillin-resistant Staphylococcus aureus lineages. Clin. Microbiol. Rev. 36, e0014822 (2023).

    Article  PubMed  Google Scholar 

  145. CARB-X Press release. CARB-X is funding a team of top German researchers to develop a drug to treat Staphylococcus aureus infections and prevent exacerbation of life-threatening pneumonia. https://carb-x.org/carb-x-news/carb-x-is-funding-a-team-of-top-german-researchers-to-develop-a-drug-to-treat-staphylococcus-aureus-infections-and-prevent-exacerbation-of-life-threatening-pneumonia/ (2020).

  146. Baković, J. et al. Redox regulation of the quorum-sensing transcription factor AgrA by coenzyme A. Antioxidants 10, 841 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Trebosc, V. et al. In vitro activity of BV200 anti-virulent small molecules against a large and geographically diverse panel of S. aureus isolates from skin and lung infections. Presented at 32nd European Congress of Clinical Microbiology & Infectious Diseases (2022).

  148. Horna, G. & Ruiz, J. Type 3 secretion system of Pseudomonas aeruginosa. Microbiol. Res. 246, 126719 (2021).

    Article  CAS  PubMed  Google Scholar 

  149. Moir, D. T. et al. A structure-function-inhibition analysis of the Pseudomonas aeruginosa type III secretion needle protein PscF. J. Bacteriol. 202, e00055-20 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Simonis, A. et al. Discovery of highly neutralizing human antibodies targeting Pseudomonas aeruginosa. Cell 186, 5098–5113.e19 (2023).

    Article  CAS  PubMed  Google Scholar 

  151. Elmassry, M. M., Colmer-Hamood, J. A., Kopel, J., San Francisco, M. J. & Hamood, A. N. Anti-Pseudomonas aeruginosa vaccines and therapies: an assessment of clinical trials. Microorganisms 11, 916 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Williams, J. D. et al. Synthesis and structure–activity relationships of novel phenoxyacetamide inhibitors of the Pseudomonas aeruginosa type III secretion system (T3SS). Bioorg Med. Chem. 23, 1027–1043 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Berube, B. J. et al. Impact of type III secretion effectors and of phenoxyacetamide inhibitors of type III secretion on abscess formation in a mouse model of Pseudomonas aeruginosa infection. Antimicrob. Agents. Chemother. 61, e01202-17 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Strathdee, S. A., Hatfull, G. F., Mutalik, V. K. & Schooley, R. T. Phage therapy: from biological mechanisms to future directions. Cell 186, 17–31 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Hitchcock, N. M. et al. Current clinical landscape and global potential of bacteriophage therapy. Viruses 15, 1020 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Green, S. I. et al. A retrospective, observational study of 12 cases of expanded-access customized phage therapy: production, characteristics, and clinical outcomes. Clin. Infect. Dis. 77, 1079–1091 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Szijártó, V. et al. Bactericidal monoclonal antibodies specific to the lipopolysaccharide O antigen from multidrug-resistant Escherichia coli clone ST131-O25b:H4 elicit protection in mice. Antimicrob. Agents Chemother. 59, 3109–3116 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Bruno, J. G. Applications in which aptamers are needed or wanted in diagnostics and therapeutics. Pharmaceuticals 15, 693 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Kristian, S. A. et al. Retargeting pre-existing human antibodies to a bacterial pathogen with an alpha-Gal conjugated aptamer. J. Mol. Med. 93, 619–631 (2015).

    Article  CAS  PubMed  Google Scholar 

  160. Chadborn, T. et al. An approach for embedding behavioural science in antimicrobial resistance One Health research. J. Infect. Public Health 16, 134–140 (2023).

    Article  PubMed  Google Scholar 

  161. Lewnard, J. A. et al. Burden of bacterial antimicrobial resistance in low-income and middle-income countries avertible by existing interventions: an evidence review and modelling analysis. Lancet 403, 2439–2454 (2024).

    Article  PubMed  Google Scholar 

  162. Mendelson, M. et al. Antimicrobial resistance and the great divide: inequity in priorities and agendas between the Global North and the Global South threatens global mitigation of antimicrobial resistance. Lancet Glob. Health 12, e516–e521 (2024).

    Article  CAS  PubMed  Google Scholar 

  163. Theuretzbacher, U. et al. Critical analysis of antibacterial agents in clinical development. Nat. Rev. Microbiol. 18, 286–298 (2020).

    Article  CAS  PubMed  Google Scholar 

  164. Paterson, D. L. Antibacterial agents active against Gram negative bacilli in phase I, II, or III clinical trials. Expert Opin. Investig. Drugs 33, 371–387 (2024).

    Article  CAS  PubMed  Google Scholar 

  165. McDowell, L. L., Quinn, C. L., Leeds, J. A., Silverman, J. A. & Silver, L. L. Perspective on antibacterial lead identification challenges and the role of hypothesis-driven strategies. SLAS Discov. 24, 440–456 (2019).

    Article  CAS  PubMed  Google Scholar 

  166. Miethke, M. et al. Towards the sustainable discovery and development of new antibiotics. Nat. Rev. Chem. 5, 726–749 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Piddock, L. J. V., Malpani, R. & Hennessy, A. Challenges and opportunities with antibiotic discovery and exploratory research. ACS Infect. Dis. 10, 2445–2447 (2024).

    Article  CAS  PubMed  Google Scholar 

  168. Silver, L. L. Challenges of antibacterial discovery. Clin. Microbiol. Rev. 24, 71–109 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Theuretzbacher, U., Baraldi, E., Ciabuschi, F. & Callegari, S. Challenges and shortcomings of antibacterial discovery projects. Clin. Microbiol. Inf. 29, 610–615 (2023).

    Article  Google Scholar 

  170. Theuretzbacher, U. Antibiotic innovation for future public health needs. Clin. Microbiol. Inf. 23, 713–717 (2017).

    Article  CAS  Google Scholar 

  171. Butler, M. S., Henderson, I. R., Capon, R. J. & Blaskovich, M. A. T. Antibiotics in the clinical pipeline as of December 2022. J. Antibiot. 76, 431–473 (2023).

    Article  CAS  Google Scholar 

  172. Butler, M. S. et al. Analysis of the clinical pipeline of treatments for drug-resistant bacterial infections: despite progress, more action is needed. Antimicrob. Agents Chemother. 66, e0199121 (2022).

    Article  PubMed  Google Scholar 

  173. Theuretzbacher, U., Outterson, K., Engel, A. & Karlén, A. The global preclinical antibacterial pipeline. Nat. Rev. Microbiol. 18, 275–285 (2020).

    Article  PubMed  Google Scholar 

  174. Bergkessel, M., Forte, B. & Gilbert, I. H. Small-molecule antibiotic drug development: need and challenges. ACS Infect. Dis. 9, 2062–2071 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Cohn, J. et al. Improving equitable access for effective antibacterial: an ecosystem approach. Clin. Microbiol. Infect. 31, 339–344 (2025).

    Article  PubMed  Google Scholar 

  176. Cohn, J. et al. Accelerating antibiotic access and stewardship: a new model to safeguard public health. Lancet Infect. Dis. 24, e584–e590 (2024).

    Article  PubMed  Google Scholar 

  177. Tacconelli, E. et al. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect. Dis. 18, 318–327 (2018).

    Article  PubMed  Google Scholar 

  178. Martínez, J. L., Baquero, F. & Andersson, D. I. Beyond serial passages: new methods for predicting the emergence of resistance to novel antibiotics. Curr. Opin. Pharmacol. 11, 439–445 (2011).

    Article  PubMed  Google Scholar 

  179. Kaplan, N. et al. Mode of action, in vitro activity, and in vivo efficacy of AFN-1252, a selective antistaphylococcal FabI inhibitor. Antimicrob. Agents Chemother. 56, 5865–5874 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Hill, A. M., Barber, M. J. & Gotham, D. Estimated costs of production and potential prices for the WHO Essential Medicines List. BMJ Glob. Health 3, e000571 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank M. Duffey, GARDP, for generating the draft of Fig. 4.

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Authors and Affiliations

  1. Center for Anti-Infective Agents, Vienna, Austria

    Ursula Theuretzbacher

  2. Global Antibiotic Research and Development Partnership, Geneva, Switzerland

    Ravindra P. Jumde, Alan Hennessy, Jennifer Cohn & Laura J. V. Piddock

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Theuretzbacher, U., Jumde, R.P., Hennessy, A. et al. Global health perspectives on antibacterial drug discovery and the preclinical pipeline. Nat Rev Microbiol 23, 474–490 (2025). https://doi.org/10.1038/s41579-025-01167-w

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