Discovery of MRSA active antibiotics using primary sequence from the human microbiome

John Chu, Xavier Vila-Farres, Daigo Inoyama, Melinda Ternei, Louis J. Cohen, Emma A. Gordon, Boojala Vijay B. Reddy, Zachary Charlop-Powers, Henry A. Zebroski, Ricardo Gallardo-Macias, Mark Jaskowski, Shruthi Satish, Steven Park, David S. Perlin, Joel S. Freundlich, Sean F. Brady

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

Abstract

Here we present a natural product discovery approach, whereby structures are bioinformatically predicted from primary sequence and produced by chemical synthesis (synthetic-bioinformatic natural products, syn-BNPs), circumventing the need for bacterial culture and gene expression. When we applied the approach to nonribosomal peptide synthetase gene clusters from human-associated bacteria, we identified the humimycins. These antibiotics inhibit lipid II flippase and potentiate β-lactam activity against methicillin-resistant Staphylococcus aureus in mice, potentially providing a new treatment regimen.

Original languageEnglish (US)
Pages (from-to)1004-1006
Number of pages3
JournalNature Chemical Biology
Volume12
Issue number12
DOIs
StatePublished - Dec 1 2016
Externally publishedYes

Bibliographical note

Funding Information:
We thank members of the Fischetti (MRSA), Tomasz (MRSA) and Marraffini (S. aureus, S. delphini, S. intermedius, and S. pseudo-intermedius) laboratories at the Rockefeller University for providing strains. This work was supported by the Rainin Foundation, US National Institutes of Health grants U19AI109713 (D.S.P.) and F32 29 AI110029 (Z.C.-P.).

Publisher Copyright:
© 2016 Nature America, Inc., part of Springer Nature.

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