Skip to main content

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.

  • Review Article
  • Published:

The global preclinical antibacterial pipeline

Nature Reviews Microbiology volume 18, pages 275–285 (2020)Cite this article

Subjects

Abstract

Antibacterial resistance is a great concern and requires global action. A critical question is whether enough new antibacterial drugs are being discovered and developed. A review of the clinical antibacterial drug pipeline was recently published, but comprehensive information about the global preclinical pipeline is unavailable. This Review focuses on discovery and preclinical development projects and has found, as of 1 May 2019, 407 antibacterial projects from 314 institutions. The focus is on Gram-negative pathogens, particularly bacteria on the WHO priority bacteria list. The preclinical pipeline is characterized by high levels of diversity and interesting scientific concepts, with 135 projects on direct-acting small molecules that represent new classes, new targets or new mechanisms of action. There is also a strong trend towards non-traditional approaches, including diverse antivirulence approaches, microbiome-modifying strategies, and engineered phages and probiotics. The high number of pathogen-specific and adjunctive approaches is unprecedented in antibiotic history. Translational hurdles are not adequately addressed yet, especially development pathways to show clinical impact of non-traditional approaches. The innovative potential of the preclinical pipeline compared with the clinical pipeline is encouraging but fragile. Much more work, focus and funding are needed for the novel approaches to result in effective antibacterial therapies to sustainably combat antibacterial resistance.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Overview of the preclinical antibacterial pipeline.
Fig. 2: Type and location of institutions that carry out preclinical antibacterial development.
Fig. 3: Antibacterial approaches, development phase, indications and routes of administration in the preclinical pipeline.
Fig. 4: Approaches and spectrum of preclinical direct-acting, small-molecule antibacterials.
Fig. 5: Phages and phage-derived therapeutics, microbiota-modulating approaches and antivirulence approaches in the preclinical pipeline.

Similar content being viewed by others

References

  1. Lobanovska, M. & Pilla, G. Penicillin's discovery and antibiotic resistance: lessons for the future? Yale J. Biol. Med. 90, 135–145 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Aminov, R. I. A brief history of the antibiotic era: lessons learned and challenges for the future. Front. Microbiol. 1, 134–134 (2010).

    PubMed  PubMed Central  Google Scholar 

  3. Podolsky, S. H. The antibiotic era: reform, resistance, and the pursuit of a rational therapeutics. (John Hopkins University Press, 2015).

    Google Scholar 

  4. Baker, S. J., Payne, D. J., Rappuoli, R. & De Gregorio, E. Technologies to address antimicrobial resistance. Proc. Natl Acad. Sci. USA 115, 12887–12895 (2018). Extensive review of past antibacterial therapies and opportunities for future strategies to provide new therapies.

    CAS  PubMed  Google Scholar 

  5. Cars, O. Securing access to effective antibiotics for current and future generations. Whose responsibility? Ups J. Med. Sci. 119, 209–214 (2014).

    PubMed  PubMed Central  Google Scholar 

  6. Interagency Coordination Group on Antimicrobial Resistance. No time to wait: securing the future from drug-resistant infections. Report to the Secretary-General of the United Nations. https://www.who.int/antimicrobial-resistance/interagency-coordination-group/IACG_final_report_EN.pdf (2019).

  7. Theuretzbacher, U. et al. Analysis of the clinical antibacterial and antituberculosis pipeline. Lancet Infect. Dis. 19, e40–e50 (2019).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  9. Wellcome Trust & The Boston Consulting Group. Vaccines to tackle drug resistant infections. An evaluation of R&D opportunities, https://vaccinesforamr.org (2019).

  10. Kortright, K. E., Chan, B. K., Koff, J. L. & Turner, P. E. Phage therapy: a renewed approach to combat antibiotic-resistant bacteria. Cell Host Microbe 25, 219–232 (2019).

    CAS  PubMed  Google Scholar 

  11. Motley, M. P. & Fries, B. C. A new take on an old remedy: generating antibodies against multidrug-resistant gram-negative bacteria in a postantibiotic world. mSphere 2, e00397–00317 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Miró-Canturri, A., Ayerbe-Algaba, R. & Smani, Y. Drug repurposing for the treatment of bacterial and fungal infections. Front Microbiol. 10, 41 (2019).

    PubMed  PubMed Central  Google Scholar 

  13. Rello, J., Parisella, F. R. & Perez, A. Alternatives to antibiotics in an era of difficult-to-treat resistance: new insights. Expert Rev. Clin. Pharmacol. 12, 635–642 (2019).

    CAS  PubMed  Google Scholar 

  14. Monserrat-Martinez, A., Gambin, Y. & Sierecki, E. Thinking outside the bug: molecular targets and strategies to overcome antibiotic resistance. Int. J. Mol. Sci. 20, E1255 (2019). An extensive overview of past and current strategies for antibacterial therapies.

    PubMed  Google Scholar 

  15. Domalaon, R., Idowu, T., Zhanel, G. G. & Schweizer, F. Antibiotic hybrids: the next generation of agents and adjuvants against gram-negative pathogens? Clin. Microbiol. Rev. 31, e00077–17 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Kohanski, M. A., Dwyer, D. J. & Collins, J. J. How antibiotics kill bacteria: from targets to networks. Nat. Rev. Microbiol. 8, 423–435 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 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).

    CAS  PubMed  Google Scholar 

  18. Ciumac, D., Gong, H., Hu, X. & Lu, J. R. Membrane targeting cationic antimicrobial peptides. J. Colloid. Interface Sci. 537, 163–185 (2019).

    CAS  PubMed  Google Scholar 

  19. Ma, C., Yang, X. & Lewis, P. J. Bacterial transcription as a target for antibacterial drug development. Microbiol. Mol. Biol. Rev. 80, 139–160 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Silver, L. L. Appropriate targets for antibacterial drugs. Cold Spring Harb. Perspect. Med. 6, a030239 (2016).

    PubMed  PubMed Central  Google Scholar 

  21. 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). The WHO list prioritizes target pathogens for antibacterial drug research and discovery with a global perspective.

    PubMed  Google Scholar 

  22. Kang, H.-K., Kim, C., Seo, C. H. & Park, Y. The therapeutic applications of antimicrobial peptides (AMPs): a patent review. J. Microbiol. 55, 1–12 (2017).

    CAS  PubMed  Google Scholar 

  23. Molchanova, N., Hansen, P. R. & Franzyk, H. Advances in development of antimicrobial peptidomimetics as potential drugs. Molecules 22, 1430 (2017).

    PubMed Central  Google Scholar 

  24. Hoda, M. et al. Antimicrobial peptides: features, action, and their resistance mechanisms in bacteria. Microb. Drug Res. 24, 747–767 (2018).

    Google Scholar 

  25. Torres, M. D. T., Sothiselvam, S., Lu, T. K. & de la Fuente-Nunez, C. Peptide design principles for antimicrobial applications. J. Mol. Biol. 431, 3547–3567 (2019).

    CAS  PubMed  Google Scholar 

  26. Kuppusamy, R., Willcox, M., Black, D. S. & Kumar, N. Short cationic peptidomimetic antimicrobials. Antibiotics 8, 44 (2019).

    CAS  PubMed Central  Google Scholar 

  27. Wright, G. D. Opportunities for natural products in 21st century antibiotic discovery. Nat. Prod. Rep. 34, 694–701 (2017).

    CAS  PubMed  Google Scholar 

  28. Rossiter, S. E., Fletcher, M. H. & Wuest, W. M. Natural products as platforms to overcome antibiotic resistance. Chem. Rev. 117, 12415–12474 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Fedorenko, V. et al. Antibacterial discovery and development: from gene to product and back. Biomed. Res. Int. 2015, 591349–591349 (2015).

    PubMed  PubMed Central  Google Scholar 

  30. Erwin, A. L. Antibacterial drug discovery targeting the lipopolysaccharide biosynthetic enzyme LpxC. Cold Spring Harb. Perspect. Med. 6, a025304 (2016).

    PubMed  PubMed Central  Google Scholar 

  31. Fang, L. & Shutao, M. Recent process in the inhibitors of UDP-3-O-(R-3-hydroxyacyl)-nacetylglucosamine deacetylase (LpxC) against gram-negative bacteria. Mini Rev. Med. Chem. 18, 310–323 (2018).

    Google Scholar 

  32. Cohen, F. et al. Optimization of LpxC inhibitors for antibacterial activity and cardiovascular safety. Chem. Med. Chem. 14, 1560–1572 (2019).

    CAS  PubMed  Google Scholar 

  33. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT03832517 (2019).

  34. Wach, A., Dembowsky, K. & Dale, G. E. Pharmacokinetics and safety of intravenous murepavadin infusion in healthy adult subjects administered single and multiple ascending doses. Antimicrob. Agents Chemother. 62, e02355–17 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Philippon, A., Jacquier, H., Ruppe, E. & Labia, R. Structure-based classification of class a beta-lactamases, an update. Curr. Res. Transl. Med. S2452-3186, 30021–30022 (2019).

    Google Scholar 

  36. Bush, K. & Bradford, P. A. Interplay between β-lactamases and new β-lactamase inhibitors. Nat. Rev. Microbiol. 17, 295–306 (2019).

    CAS  PubMed  Google Scholar 

  37. Shi, C. et al. Approaches for the discovery of metallo-β-lactamase inhibitors: a review. Chem. Biol. Drug Des. 94, 1427–1440 (2019).

    CAS  PubMed  Google Scholar 

  38. Greene, N. P., Kaplan, E., Crow, A. & Koronakis, V. Antibiotic resistance mediated by the MacB ABC transporter family: a structural and functional perspective. Front Microb. 9, 950–950 (2018).

    Google Scholar 

  39. Lamut, A., Peterlin Mašič, L., Kikelj, D. & Tomašič, T. Efflux pump inhibitors of clinically relevant multidrug resistant bacteria. Med. Res. Rev. https://doi.org/10.1002/med.21591 (2019).

  40. Peyclit, L., Baron, S. A. & Rolain, J.-M. Drug repurposing to fight colistin and carbapenem-resistant bacteria. Front Cell Infect. Microbiol. 9, 193–193 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Rohde, C., Wittmann, J. & Kutter, E. Bacteriophages: a therapy concept against multi-drug-resistant bacteria. Surg Infect. 19, 737–744 (2018).

    Google Scholar 

  42. McCallin, S., Sacher, J. C., Zheng, J. & Chan, B. K. Current state of compassionate phage therapy. Viruses 11, 343 (2019).

    PubMed Central  Google Scholar 

  43. Morozova, V. V., Vlassov, V. V. & Tikunova, N. V. Applications of bacteriophages in the treatment of localized infections in humans. Front. Microbiol. 9, 1696–1696 (2018).

    PubMed  PubMed Central  Google Scholar 

  44. Chang, R. Y. K. et al. Phage therapy for respiratory infections. Adv. Drug Deliv. Rev. 133, 76–86 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Dąbrowska, K. Phage therapy: what factors shape phage pharmacokinetics and bioavailability? Systematic and critical review. Med. Res. Rev. https://doi.org/10.1002/med.21572 (2019). Critical challenges in treating bacterial infections at different body sites are reviewed.

  46. Hatoum-Aslan, A. Phage genetic engineering using CRISPR–Cas systems. Viruses 10, 335 (2018).

    PubMed Central  Google Scholar 

  47. Dams, D., Brøndsted, L., Drulis-Kawa, Z. & Briers, Y. Engineering of receptor-binding proteins in bacteriophages and phage tail-like bacteriocins. Biochem. Soc. Trans. 47, 449–460 (2019).

    CAS  PubMed  Google Scholar 

  48. Patsali, P., Kleanthous, M. & Lederer, C. W. Disruptive technology: CRISPR/Cas-based tools and approaches. Mol. Diagn. Ther. 23, 187–200 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Vila, J. Microbiota transplantation and/or CRISPR/Cas in the battle against antimicrobial resistance. Clin. Microbiol. Infect. 24, 684–686 (2018).

    CAS  PubMed  Google Scholar 

  50. Segall, A. M., Roach, D. R. & Strathdee, S. A. Stronger together? Perspectives on phage-antibiotic synergy in clinical applications of phage therapy. Curr. Opin. Microbiol. 51, 46–50 (2019).

    PubMed  Google Scholar 

  51. Rex, J. H., Fernandez Lynch, H., Cohen, G., Darrow, J. J. & Outterson, K. Designing development programs for non-traditional antibacterial agents. Nat. Commun. 10, 3416 (2019).

    PubMed  PubMed Central  Google Scholar 

  52. Fischetti, V. A. Development of phage lysins as novel therapeutics: a historical perspective. Viruses 10, 310 (2018).

    PubMed Central  Google Scholar 

  53. Abdelkader, K., Gerstmans, H., Saafan, A., Dishisha, T. & Briers, Y. The preclinical and clinical progress of bacteriophages and their lytic enzymes: the parts are easier than the whole. Viruses 11, 96 (2019).

    CAS  PubMed Central  Google Scholar 

  54. Oliveira, H., São-José, C. & Azeredo, J. Phage-derived peptidoglycan degrading enzymes: challenges and future prospects for in vivo therapy. Viruses 10, 292 (2018).

    PubMed Central  Google Scholar 

  55. Briers, Y. & Lavigne, R. Breaking barriers: expansion of the use of endolysins as novel antibacterials against gram-negative bacteria. Future Microbiol. 10, 377–390 (2015).

    CAS  PubMed  Google Scholar 

  56. Falony, G. et al. The human microbiome in health and disease: hype or hope. Acta Clin. Belg. 74, 53–64 (2019). Recent gut microbiome research may help to accelerate translation of microbiome findings from bench to bedside.

    PubMed  Google Scholar 

  57. Cammarota, G. et al. European consensus conference on faecal microbiota transplantation in clinical practice. Gut 66, 569–580 (2017).

    PubMed  PubMed Central  Google Scholar 

  58. FDA. FDA In Brief: FDA warns about potential risk of serious infections caused by multi-drug resistant organisms related to the investigational use of fecal microbiota for transplantation. https://www.fda.gov/news-events/fda-brief/fda-brief-fda-warns-about-potential-risk-serious-infections-caused-multi-drug-resistant-organisms (2019).

  59. Kellermayer, R. Fecal microbiota transplantation: great potential with many challenges. Transl. Gastroenterol. Hepatol. 4, 40–40 (2019).

    PubMed  PubMed Central  Google Scholar 

  60. Iqbal, U., Anwar, H. & Karim, M. A. Safety and efficacy of encapsulated fecal microbiota transplantation for recurrent clostridium difficile infection: a systematic review. Eur. J. Gastroenterol. Hepatol. 30, 730–734 (2018).

    PubMed  Google Scholar 

  61. Mathipa, M. G. & Thantsha, M. S. Probiotic engineering: towards development of robust probiotic strains with enhanced functional properties and for targeted control of enteric pathogens. Gut Pathog. 9, 28–28 (2017).

    PubMed  PubMed Central  Google Scholar 

  62. Ghosh, C., Sarkar, P., Issa, R. & Haldar, J. Alternatives to conventional antibiotics in the era of antimicrobial resistance. Trends Microbiol. 27, 323–338 (2019).

    CAS  PubMed  Google Scholar 

  63. Ozdemir, T., Fedorec, A. J. H., Danino, T. & Barnes, C. P. Synthetic biology and engineered live biotherapeutics: toward increasing system complexity. Cell Syst. 7, 5–16 (2018).

    CAS  PubMed  Google Scholar 

  64. Fehér, C., Soriano, A. & Mensa, J. A review of experimental and off-label therapies for clostridium difficile infection. Infect. Dis. Ther. 6, 1–35 (2017).

    PubMed  Google Scholar 

  65. Connelly, S., Fanelli, B., Hasan, N. A., Colwell, R. R. & Kaleko, M. Oral metallo-beta-lactamase protects the gut microbiome from carbapenem-mediated damage and reduces propagation of antibiotic resistance in pigs. Front Microbiol. 10, 101–101 (2019).

    PubMed  PubMed Central  Google Scholar 

  66. Ramachandran, G. & Bikard, D. Editing the microbiome the CRISPR way. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 374, 20180103 (2019). New technologies bring challenges and opportunities for future new therapies that are reviewed in this article.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Pena, R. T. et al. Relationship between quorum sensing and secretion systems. Front Microbiol. 10, 1100–1100 (2019).

    PubMed  PubMed Central  Google Scholar 

  68. Sharma, D., Misba, L. & Khan, A. U. Antibiotics versus biofilm: an emerging battleground in microbial communities. Antimicrob. Resist. Infect. Control 8, 76–76 (2019).

    PubMed  PubMed Central  Google Scholar 

  69. Murugayah, S. A. & Gerth, M. L. Engineering quorum quenching enzymes: progress and perspectives. Biochem. Soc. Trans. 47, 793–800 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Defraine, V., Fauvart, M. & Michiels, J. Fighting bacterial persistence: Current and emerging anti-persister strategies and therapeutics. Drug Resist. Updat. 38, 12–26 (2018).

    PubMed  Google Scholar 

  71. Fleitas Martínez, O., Cardoso, M. H., Ribeiro, S. M. & Franco, O. L. Recent advances in anti-virulence therapeutic strategies with a focus on dismantling bacterial membrane microdomains, toxin neutralization, quorum-sensing interference and biofilm inhibition. Front Cell Infect. Microbiol. 9, 74–74 (2019).

    PubMed  PubMed Central  Google Scholar 

  72. Maura, D., Ballok, A. E. & Rahme, L. G. Considerations and caveats in anti-virulence drug development. Curr. Opin. Microbiol. 33, 41–46 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Dickey, S. W., Cheung, G. Y. C. & Otto, M. Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance. Nat. Rev. Drug Discov. 16, 457–471 (2017).

    CAS  PubMed  Google Scholar 

  74. Aridis Pharmaceuticals, Inc. Aridis Pharmaceuticals reports phase 2 clinical trial results of AR-105 for the treatment of ventilator-associated pneumonia caused by Pseudomonas Aeruginosa. Investors.aridispharma.com. https://investors.aridispharma.com/2019-09-03-Aridis-Pharmaceuticals-Reports-Phase-2-Clinical-Trial-Results-of-AR-105-for-the-Treatment-of-Ventilator-Associated-Pneumonia-Caused-by-Pseudomonas-Aeruginosa (2019).

  75. Redi, D., Raffaelli, C. S., Rossetti, B., De Luca, A. & Montagnani, F. Staphylococcus aureus vaccine preclinical and clinical development: current state of the art. New Microbiol. 41, 208–213 (2018).

    CAS  PubMed  Google Scholar 

  76. Priebe, G. P. & Goldberg, J. B. Vaccines for pseudomonas aeruginosa: a long and winding road. Expert Rev. Vaccines 13, 507–519 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Canaparo, R. et al. Recent developments in antibacterial therapy: focus on stimuli-responsive drug-delivery systems and therapeutic nanoparticles. Molecules 24, 1991 (2019).

    CAS  PubMed Central  Google Scholar 

  78. Kwon, E. J. et al. Porous silicon nanoparticle delivery of tandem peptide anti-infectives for the treatment of pseudomonas aeruginosa lung infections. Adv. Mater. 29, 1701527 (2017).

    Google Scholar 

  79. Kumar, M., Curtis, A. & Hoskins, C. Application of nanoparticle technologies in the combat against anti-microbial resistance. Pharmaceutics. 10, 11 (2018).

    PubMed Central  Google Scholar 

  80. Theuretzbacher, U. & Paul, M. Developing a new antibiotic for extensively drug-resistant pathogens: the case of plazomicin. Clin. Microbiol. Inf. 24, 1231–1233 (2018).

    CAS  Google Scholar 

  81. Czaplewski, L. et al. Alternatives to antibiotics-a pipeline portfolio review. Lancet Infect. Dis. 16, 239–251 (2016).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

U.T. received federal funds from the German Federal Ministry of Education and Research (BMBF) to support this Review. The funder had no role in study design, data collection, data analysis, data interpretation or writing of the article. K.O. is Principal Investigator and Executive Director of CARB-X, funded by Notice of Award 5IDSEP160030-04-00 from the US Biomedical Advanced Research and Development Authority (Assistant Secretary for Preparedness and Response, Department of Health and Human Services), preclinical services from the US National Institute for Allergy and Infectious Diseases (National Institutes of Health, Department of Health and Human Services) and funding from the Wellcome Trust, the German Federal Ministry for Education and Research (BMBF), the Global AMR Innovation Fund from the UK Department of Health and Social Care and the Bill & Melinda Gates Foundation. A.E. is a partner with Novo Holdings A/S and Director of the REPAIR Impact Fund, which was commissioned by the Novo Nordisk Foundation. A.K. is the leader of the managing entity of the ENABLE consortium and has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115583, resources of which are composed of financial contributions from the European Union’s seventh framework programme and European Federation of Pharmaceutical Industries and Associations companies’ in-kind contribution. Those projects in ENABLE that volunteered information for this Review are gratefully acknowledged. The views herein do not necessarily represent the view of the ENABLE partners. The views expressed herein do not necessarily represent the views of CARB-X or any CARB-X funder, the REPAIR Impact Fund or ENABLE or any of its funders. The authors thank L. Marin for providing data from the Joint Programming Initiative on Antimicrobial Resistance.

Author information

Authors and Affiliations

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

    Ursula Theuretzbacher

  2. Boston University, Boston, MA, USA

    Kevin Outterson

  3. CARB-X, Boston, MA, USA

    Kevin Outterson

  4. Novo Holding A/S, Copenhagen, Denmark

    Aleks Engel

  5. Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden

    Anders Karlén

Authors
  1. Ursula Theuretzbacher
    View author publications

    Search author on:PubMed Google Scholar

  2. Kevin Outterson
    View author publications

    Search author on:PubMed Google Scholar

  3. Aleks Engel
    View author publications

    Search author on:PubMed Google Scholar

  4. Anders Karlén
    View author publications

    Search author on:PubMed Google Scholar

Contributions

A.E. provided the data from the REPAIR Impact Fund. K.O. provided the data from CARB-X. A.K. provided the data from ENABLE. U.T. provided the data from the Center for Anti-Infective Agents (CEFAIA). All data was provided to U.T. for application of the inclusion criteria, descriptive results, analysis and discussion of the findings. U.T. wrote the first draft and K.O. provided the first comprehensive edit, which was then reviewed and edited by all authors.

Corresponding author

Correspondence to Ursula Theuretzbacher.

Ethics declarations

Competing interests

The 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.

Related links

CARB-X: https://carb-x.org/portfolio/gallery/

ENABLE: http://nd4bb-enable.eu/enable-portfolio

Joint Programming Initiative on Antimicrobial Resistance: https://www.jpiamr.eu/supportedprojects/

Pew Trusts: https://www.pewtrusts.org/en/research-and-analysis/articles/2018/09/21/the-shared-platform-for-antibiotic-research-and-knowledge

REPAIR Impact Fund: https://www.repair-impact-fund.com/portfolio/

Supplementary information

Glossary

Lead generation phase (hit-to-lead phase)

Drug discovery phase where promising molecules (hits) are evaluated and undergo limited optimization to identify suitable lead compounds.

Repurposed approved drugs

Repurposing a drug is a strategy for identifying new uses for an approved drug that are outside the scope of the original indication.

Label expansion

Aims to achieve additional regulatory approval for a new indication beyond the original use for which the drug was approved.

Indications

A therapeutic indication refers to the use of a drug for treating a particular disease. The indication can be approved by regulatory agencies or not approved.

Spectrum

Range of activity against a group of bacteria.

Formulations

Pharmaceutical formulation is the process in which the active compound and additional ingredients are combined to produce a final medicinal product.

Parenteral application

Route of administration other than the gastrointestinal tract to achieve systemic distribution.

Intravesical application

Administration of a drug directly into the bladder.

Non-fermenters

Heterogeneous group of bacteria which cannot use glucose and thus are unable to generate energy through fermentation of glucose. Important genera of non-fermenters include Pseudomonas and Acinetobacter.

Phase III trials

In clinical development, phase III clinical trials are randomized controlled multicentre studies that assess the effectiveness and safety of a drug in comparison to current standard-of-care treatment.

Metallo-ß-lactamases

ß-Lactamases that require zinc for activity and hydrolyse penicillins, cephalosporins and carbapenems.

Endolysins

Enzymes that are produced by bacteriophages and hydrolyse the bacterial cell wall to escape the cell at the end of the cycle.

Compassionate use

The use of unapproved drugs outside clinical trials for patients without options of treatment with an approved drug.

Push funding

Incentivizes discovery and development activities before achieving regulatory approval.

Pull incentives

Reward the successful development and regulatory approval of a new drug.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Theuretzbacher, U., Outterson, K., Engel, A. et al. The global preclinical antibacterial pipeline. Nat Rev Microbiol 18, 275–285 (2020). https://doi.org/10.1038/s41579-019-0288-0

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41579-019-0288-0

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing