Skip to main content

Thank you for visiting 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.

Opinion — anti-infectives

Where will new antibiotics come from?


There is a constant need for new antibacterial drugs owing to the inevitable development of resistance that follows the introduction of antibiotics to the clinic. When a new class of antibiotic is introduced, it is effective at first, but will eventually select for survival of the small fraction of bacterial populations that have an intrinsic or acquired resistance mechanism. Pathogens that are resistant to multiple drugs emerge around the globe, so how robust are antibiotic discovery processes?

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Structures of naturally and synthetically derived antibiotics.
Figure 2: Principal targets for antibiotic action.


  1. Thornsberry, C. et al. Regional trends in antimicrobial resistance among clinical isolates of Streptococcus pneumoniae, Haemophlius influenzae, and Moraxella catarrhalis in the United States: results from the TRUST Surveillance Program, 1999–2000. Clin. Infect. Dis. 34, S4–S16 (2002).

    Article  PubMed  Google Scholar 

  2. Palumbi, S. R. Humans as the world's greatest evolutionary force. Science 293, 1786–1790 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Walsh, C. T. Antibiotics: Actions, Origins, Resistance. (ASM Press, Washington DC, USA, 2003).

    Book  Google Scholar 

  4. Coates, A., Hu, Y., Bax, R. & Page,C. The future challenges facing the development of new antimicrobial drugs. Nature Rev. Drug Discov. 1, 895–910 (2002).

    Article  CAS  Google Scholar 

  5. Tally, F. P. & DeBruin, M. F. Development of daptomycin for gram-positive infections. J. Antimicrob. Chemother. 46, 523–526 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. MacNeil, I. A. et al. Expression and isolation of small molecules from soil DNA libraries. J. Mol. Microbiol. Biotechnol. 3, 301–308 (2001).

    CAS  PubMed  Google Scholar 

  7. Khosla, C. Harnessing the biosynthetic potential of modular polyketide synthases. Chem. Rev. 97, 2577–2590 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Cane, D. E., Walsh, C. T. & Khosla, C. Harnessing the biosynthetic code; combinations, permutations, and mutations. Science 282, 63–68 (1998).

    Article  CAS  Google Scholar 

  9. Howe, R. A. & Spencer, R. C. Cotrimoxazole, rationale for re-examining its indications for use. Drug Saf. 14, 213–218 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Scholar, E. M. & Pratt, W. B. The Antimicrobial Drugs 2nd edn (Oxford Univ. Press, New York, 2000).

    Google Scholar 

  11. Maxwell, A. DNA Gyrase as a drug target. Trends Microbiol 5, 102–109 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Arya, P. D., Chou, T. H. & Baek, M. G. Diversity-based organic synthesis in the era of genomics and proteomics. Angew. Chem. Int. Ed. 40, 339–346 (2001).

    Article  CAS  Google Scholar 

  13. Arya, P. D., Joseph, R. & Chou, D. T. Toward high-throughput synthesis of complex natural product-like compounds in the genomics and proteomics age. Chem. Biol. 9, 145–146 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Schreiber, S. L. Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 287, 1964–1969 (2000).

    Article  CAS  Google Scholar 

  15. Teague, S., Leason, D., Oprea, P. D. & Davis, T. The design of leadlike combinatorial libraries Angew. Chem. Int. Ed. 38, 3743–3748 (1999).

    Article  CAS  Google Scholar 

  16. McDaniel, R. A. et al. Multiple genetic modifications of the erythromycin polyketide synthase to produce a library of “unnatural” natural products. Proc. Natl Acad. Sci. USA 96, 1846–1851 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Walsh, C. T. Combinatorial biosynthesis of antibiotics: challenges and opportunities. Chem. Biochem. 3, 124–134 (2002).

    CAS  Google Scholar 

  18. Carter, A. P. et al. Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics. Nature 407, 340–348 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Hansen, J. L. et al. The structures of four macrolide antibiotics bound to the large ribosomal subunit. Mol. Cell 10, 117–128 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Pioletti, M. et al. Crystal structures of complexes of the small ribosomal subunit with tetracycline, edeine, and IF3. EMBO J. 20, 1829–1839 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Schlunzen, F. R. et al. Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria. Nature 413, 814–821 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Peterson, T. D. et al. The comprehensive microbial resource. Nucl. Acids Res. 29, 123–125 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Ji, Y. B. et al. Identification of critical staphylococcal genes using conditional phenotypes generated by antisense RNA. Science 293, 2266–2269 (2001).

    Article  CAS  Google Scholar 

  24. McDevitt, D. & Rosenberg, M. Exploiting genomics to discover new antibiotics. Trends Microbiol. 9, 611–617 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Ye, X. Y. et al. Better substrates for bacterial transglycosylases. J. Am. Chem. Soc. 123, 3155–3156 (2001).

    Article  CAS  Google Scholar 

  26. Yusupov, M. M. et al. Crystal structure of the ribosome at 5.5-Å resolution. Science 292, 883–896 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Navarre, W. W. & Schneewind, O. Surface proteins of gram-positive bacteria and mechanisms of their targeting to the cell wall envelope. Microbiol. Mol. Biol. Rev. 63, 174–229 (1999).

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Pallen, M. J., Lam, A. C., Antonio, M. & Dunbar, K. An embarrassment of sortases-a richness of substrates? Trends Microbiol. 9, 97–102 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Rohdich, F., Kis, K., Bacher, A. & Eisenreich, W. The non-mevalonate pathway of isoprenoids: genes, enzymes, and intermediates. Curr. Opin. Chem. Biol. 5, 535–540 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Murray, B. E. Vancomcyin-resistant enterococcal infections New Eng. J. Med. 342, 710–721 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Bonhoeffer, S., Lipsitch, M. & Levin, B. R. Evaluating treatment protocols to prevent antibiotic resistance. Proc. Natl Acad. Sci. USA 94, 12106–12111 (1997).

    Article  CAS  PubMed  Google Scholar 

  32. Shlaes, D. et al. Guidelines for the prevention of antimicrobial resistance in hospitals. Clin. Infect. Dis. 25, 584–599 (1997).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations


Related links

Related links


Christopher Walsh's laboratory


United States Center for Disease Control

United States Food and Drug Administration

Wellcome Trust Sanger Institute



A structural analogue of metabolites that inhibit enzymes that normally recognize the metabolite as substrate.


The application of synthetic methods, often in high-throughput format, to combine molecular fragments to create many structurally related congeners.


A drug molecule that contains carbon, nitrogen, oxygen and sulphur atoms in ring structures — typically five- or six-membered rings.


Macrocyclic (ring greater than six carbons) structures in which the cyclization occurs by lactone formation between the two ends of the molecule. The macrolactone erythronolide provides the scaffold in the antibiotic erythromycin.


The collective genomes of soil bacteria.


The structural and architectural platform of natural products that can be decorated, for example, by glycosylation or with synthetic modifications.


A peptide that is made from amino acids, often amino acids that are not found in proteins, that are assembled by multimodular enzymes not involving RNA templates or the ribosome for peptide-bond formation.


A natural product that is assembled from malonyl CoA units through intermediates with many ketone (polyketonic) groups that allow for directed reactivity to product structures.


An enzyme in the cell membrane of Gram-positive bacteria that sorts proteins to be displayed in the outer membrane by covalently connecting those proteins to the peptidoglycan layer.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Walsh, C. Where will new antibiotics come from?. Nat Rev Microbiol 1, 65–70 (2003).

Download citation

  • Issue Date:

  • DOI:

This article is cited by


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