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.

Platensimycin is a selective FabF inhibitor with potent antibiotic properties

Abstract

Bacterial infection remains a serious threat to human lives because of emerging resistance to existing antibiotics. Although the scientific community has avidly pursued the discovery of new antibiotics that interact with new targets, these efforts have met with limited success since the early 1960s1,2. Here we report the discovery of platensimycin, a previously unknown class of antibiotics produced by Streptomyces platensis. Platensimycin demonstrates strong, broad-spectrum Gram-positive antibacterial activity by selectively inhibiting cellular lipid biosynthesis. We show that this anti-bacterial effect is exerted through the selective targeting of β-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II (FabF/B) in the synthetic pathway of fatty acids. Direct binding assays show that platensimycin interacts specifically with the acyl-enzyme intermediate of the target protein, and X-ray crystallographic studies reveal that a specific conformational change that occurs on acylation must take place before the inhibitor can bind. Treatment with platensimycin eradicates Staphylococcus aureus infection in mice. Because of its unique mode of action, platensimycin shows no cross-resistance to other key antibiotic-resistant strains tested, including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant enterococci. Platensimycin is the most potent inhibitor reported for the FabF/B condensing enzymes, and is the only inhibitor of these targets that shows broad-spectrum activity, in vivo efficacy and no observed toxicity.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Characterization of platensimycin.
Figure 2: Interactions of platensimycin with ecFabF(C163Q) and comparison with the apo structure.

Accession codes

Primary accessions

Protein Data Bank

References

  1. Singh, S. B. & Barrett, J. F. Empirical antibacterial drug discovery—foundation in natural products. Biochem. Pharmacol. 71, 1006–1015 (2006)

    Article  CAS  PubMed  Google Scholar 

  2. Butler, M. S. & Buss, A. D. Natural products—the future scaffolds for novel antibiotics? Biochem. Pharmacol. 71, 919–929 (2006)

    Article  CAS  PubMed  Google Scholar 

  3. Campbell, J. W. & Cronan, J. E. Bacterial fatty acid biosynthesis: Targets for antibacterial drug discovery. Annu. Rev. Microbiol. 55, 305–332 (2001)

    Article  CAS  Google Scholar 

  4. Zhang, Y.-M., Marrakchi, H., White, S. W. & Rock, C. O. The application of computational methods to explore the diversity and structure of bacterial fatty acid synthase. J. Lipid Res. 44, 1–10 (2003)

    Article  PubMed  Google Scholar 

  5. Heath, R. J. & Rock, C. O. Fatty acid biosynthesis as a target for novel antibacterials. Curr. Opin. Investig. Drugs 5, 146–153 (2004)

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Smith, S., Witkowski, A. & Joshi, A. K. Structural and functional organization of the animal fatty acid synthase. Prog. Lipid Res. 42, 289–317 (2003)

    Article  CAS  PubMed  Google Scholar 

  7. White, S. W., Zheng, J., Zhang, Y. M. & Rock, C. O. The structural biology of type II fatty acid biosynthesis. Annu. Rev. Biochem. 74, 791–831 (2005)

    Article  CAS  PubMed  Google Scholar 

  8. Revill, W. P., Bibb, M. J., Scheu, A. K., Kieser, H. J. & Hopwood, D. A. Beta-ketoacyl acyl carrier protein synthase III (FabH) is essential for fatty acid biosynthesis in Streptomyces coelicolor A3(2). J. Bacteriol. 183, 3526–3530 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lai, C.-Y. & Cronan, J. E. β-Ketoacyl-acyl carrier protein synthase III (FabH) is essential for bacterial fatty acid synthesis. J. Biol. Chem. 278, 51494–51503 (2003)

    Article  CAS  PubMed  Google Scholar 

  10. Tsay, J., Rock, C. & Jackowski, S. Overproduction of beta-ketoacyl-acyl carrier protein synthase I imparts thiolactomycin resistance to Escherichia coli K-12. J. Bacteriol. 174, 508–513 (1992)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Schujman, G. E., Choi, K. H., Altabe, S., Rock, C. O. & de Mendoza, D. Response of Bacillus subtilis to cerulenin and acquisition of resistance. J. Bacteriol. 183, 3032–3040 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Matsumae, A., Nomura, S. & Hata, T. Studies on cerulenin. IV. Biological characteristics of cerulenin. J. Antibiot. (Tokyo) 17, 1–7 (1964)

    CAS  Google Scholar 

  13. Noto, T., Miyakawa, S., Oishi, H., Endo, H. & Okazaki, H. Thiolactomycin, a new antibiotic. III. In vitro antibacterial activity. J. Antibiot. (Tokyo) 35, 401–410 (1982)

    Article  CAS  Google Scholar 

  14. Wang, J. et al. Discovery of a small molecule that inhibits cell division by blocking Ftsz, a novel therapeutic target of antibiotics. J. Biol. Chem. 278, 44424–44428 (2003)

    Article  CAS  PubMed  Google Scholar 

  15. Young, K. et al. Discovery of FabH/FabF inhibitors from natural products. Antimicrob. Agents Chemother. 50, 519–526 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kodali, S. et al. Determination of selectivity and efficacy of fatty acid synthesis inhibitors. J. Biol. Chem. 280, 1669–1677 (2005)

    Article  CAS  PubMed  Google Scholar 

  17. Heath, R. J. & Rock, C. O. The Claisen condensation in biology. Nat. Prod. Rep. 19, 581–596 (2002)

    Article  CAS  PubMed  Google Scholar 

  18. Olsen, J. G., Kadziola, A., von Wettstein-Knowles, P., Siggaard-Andersen, M. & Larsen, S. Structures of beta-ketoacyl-acyl carrier protein synthase I complexed with fatty acids elucidate its catalytic machinery. Structure (Camb) 9, 233–243 (2001)

    Article  CAS  Google Scholar 

  19. McGuire, K. A., Siggaard-Andersen, M., Bangera, M. G., Olsen, J. G. & von Wettstein-Knowles, P. β-Ketoacyl-[acyl carrier protein] synthase I of Escherichia coli: aspects of the condensation mechanism revealed by analyses of mutations in the active site pocket. Biochemistry 40, 9836–9845 (2001)

    Article  CAS  PubMed  Google Scholar 

  20. Witkowski, A., Joshi, A. K., Lindqvist, Y. & Smith, S. Conversion of a beta-ketoacyl synthase to a malonyl decarboxylase by replacement of the active-site cysteine with glutamine. Biochemistry 38, 11643–11650 (1999)

    Article  CAS  PubMed  Google Scholar 

  21. Price, A. C. et al. Inhibition of beta-ketoacyl-acyl carrier protein synthases by thiolactomycin and cerulenin. Structure and mechanism. J. Biol. Chem. 276, 6551–6559 (2001)

    Article  CAS  PubMed  Google Scholar 

  22. Huang, W. et al. Crystal structure of beta-ketoacyl-acyl carrier protein synthase II from E. coli reveals the molecular architecture of condensing enzymes. EMBO J. 17, 1183–1191 (1998)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hunter, C. A., Singh, J. & Thornton, J. M. Pi–pi interactions: the geometry and energetics of phenylalanine–phenylalanine interactions in proteins. J. Mol. Biol. 218, 837–846 (1991)

    Article  CAS  PubMed  Google Scholar 

  24. Lee, B. & Richards, F. M. The interpretation of protein structures: estimation of static accessibility. J. Mol. Biol. 55, 379–400 (1971)

    Article  CAS  PubMed  Google Scholar 

  25. Collaborative Computational Project No. 4, The CCP4 Suite: Programs for protein crystallography. Acta Crystallogr. D Biol. Crystallogr. 50, 760–763 (1994)

    Article  Google Scholar 

Download references

Acknowledgements

Use of the IMCA-CAT beamline 17-ID (or 17-BM) at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with the Center for Advanced Radiation Sources at the University of Chicago. We thank the staff of IMCA-CAT for their able assistance in data collection. This paper is dedicated to the late John Barrett for his strong contributions to antibiotic research. Author Contributions J.W. and S.B.S. led the discovery, microbiological, biochemical characterization and natural products chemistry. S.M.S. coordinated X-ray crystallographic analysis and direct binding assay development.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Jun Wang, Stephen M. Soisson or Sheo B. Singh.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. Coordinates and structure factors for all structures presented in this paper have been deposited with the PDB under accession numbers 2GFV, 2GFW, 2GFX, and 2GFY. The authors declare no competing financial interests.

Additional information

Coordinates and structure factors for all structures presented in this paper have been deposited with the PDB under accession numbers 2GFV, 2GFW, 2GFX, and 2GFY.

Supplementary information

Supplementary Notes

This file contains Supplementary Methods, Supplementary Table 1, Supplementary Figures and additional references. (PDF 3866 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, J., Soisson, S., Young, K. et al. Platensimycin is a selective FabF inhibitor with potent antibiotic properties. Nature 441, 358–361 (2006). https://doi.org/10.1038/nature04784

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature04784

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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