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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.

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

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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.

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

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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.

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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.

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

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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

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