Brief Communication

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

  • Nature Chemical Biology 12, 10041006 (2016)
  • doi:10.1038/nchembio.2207
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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.

  • Compound

    ((S)-3-hydroxytetradecanoyl)-L-tyrosyl-L-seryl-D-tyrosyl-L-phenylalanyl-D-threonyl-L-valyl-L-valine

  • Compound

    ((S)-3-hydroxytetradecanoyl)-L-tyrosyl-L-seryl-D-tyrosyl-L-tyrosyl-D-threonyl-L-alloisoleucyl-L-valine

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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.).

Author information

Author notes

    • John Chu
    •  & Xavier Vila-Farres

    These authors contributed equally to this work.

Affiliations

  1. Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, New York, New York, USA.

    • John Chu
    • , Xavier Vila-Farres
    • , Melinda Ternei
    • , Louis J Cohen
    • , Emma A Gordon
    • , Boojala Vijay B Reddy
    • , Zachary Charlop-Powers
    •  & Sean F Brady
  2. Department of Pharmacology, Physiology, and Neuroscience, Rutgers University–New Jersey Medical School, Newark, New Jersey, USA.

    • Daigo Inoyama
    • , Ricardo Gallardo-Macias
    • , Mark Jaskowski
    • , Shruthi Satish
    •  & Joel S Freundlich
  3. Proteomics Resource Center, The Rockefeller University, New York, New York, USA.

    • Henry A Zebroski
  4. Public Health Research Institute, Rutgers University–New Jersey Medical School, Newark, New Jersey, USA.

    • Steven Park
    •  & David S Perlin

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Sean F Brady.

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Results, Supplementary Figures 1–7 and Supplementary Tables 1–6.