1. Merck Research Laboratories, Rahway, New Jersey 07065, USA
2. †Present addresses: DuPont Stine-Haskell Research Center, 1090 Elkton Road, Newark, Delaware 19711, USA (W.S.); LL Silver Consulting, 3403 Park Place, Springfield, New Jersey 07081, USA (L.L.S.)
3. *These authors contributed equally to the work
4. ‡Deceased

Correspondence to: Jun Wang^1,3 Correspondence and requests for materials should be addressed to J.W. (Email: jun_wang2@merck.com), S.M.S. (Email: stephen_soisson@merck.com) or S.B.S. (Email: sheo_singh@merck.com). 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.

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 1960s^{1, 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 -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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