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

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.

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Figure 1: Overview of the syn-BNP approach.
Figure 2: Discovery and screening of the humimycins.
Figure 3: Humimycin A and β-lactam act in synergy.

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Acknowledgements

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.).

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Authors and Affiliations

Authors

Contributions

S.F.B. conceived of the project. J.C. and X.V.-F. carried out antibiosis assays, spectrum of activity screening and resistant mutant selection. D.I., H.A.Z., R.G.-M., M.J., S.S. and J.S.F. carried out peptide synthesis on large scale. M.T. carried out genome sequencing. L.J.C. and E.A.G. screened anaerobic bacteria. B.V.B.R. and Z.C.-P. carried out bioinformatic analysis. S.P. and D.S.P. carried out mouse studies.

Corresponding author

Correspondence to Sean F Brady.

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The authors declare no competing financial interests.

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Supplementary Results, Supplementary Figures 1–7 and Supplementary Tables 1–6. (PDF 2007 kb)

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Chu, J., Vila-Farres, X., Inoyama, D. et al. Discovery of MRSA active antibiotics using primary sequence from the human microbiome. Nat Chem Biol 12, 1004–1006 (2016). https://doi.org/10.1038/nchembio.2207

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