Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

Nature Chemical Biology volume 12, pages 1004–1006 (2016)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

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.

References

  1. Newman, D.J. & Cragg, G.M. J. Nat. Prod. 79, 629–661 (2016).

    Article  CAS  Google Scholar 

  2. Charlop-Powers, Z., Milshteyn, A. & Brady, S.F. Curr. Opin. Microbiol. 19, 70–75 (2014).

    Article  CAS  Google Scholar 

  3. Piel, J. Annu. Rev. Microbiol. 65, 431–453 (2011).

    Article  CAS  Google Scholar 

  4. Rutledge, P.J. & Challis, G.L. Nat. Rev. Microbiol. 13, 509–523 (2015).

    Article  CAS  Google Scholar 

  5. Qin, J. et al. Nature 464, 59–65 (2010).

    Article  CAS  Google Scholar 

  6. Turnbaugh, P.J. et al. Nature 457, 480–484 (2009).

    Article  CAS  Google Scholar 

  7. Charlop-Powers, Z. et al. eLife 4, e05048 (2015).

    Article  Google Scholar 

  8. Doroghazi, J.R. et al. Nat. Chem. Biol. 10, 963–968 (2014).

    Article  CAS  Google Scholar 

  9. Stachelhaus, T., Mootz, H.D. & Marahiel, M.A. Chem. Biol. 6, 493–505 (1999).

    Article  CAS  Google Scholar 

  10. Minowa, Y., Araki, M. & Kanehisa, M. J. Mol. Biol. 368, 1500–1517 (2007).

    Article  CAS  Google Scholar 

  11. Rottig, M. et al. Nucleic Acids Res. 39, W362–W367 (2011).

    Article  Google Scholar 

  12. Weber, T. et al. Nucleic Acids Res. 43, W237–W243 (2015).

    Article  CAS  Google Scholar 

  13. Rausch, C., Hoof, I., Weber, T., Wohlleben, W. & Huson, D.H. BMC Evol. Biol. 7, 78 (2007).

    Article  Google Scholar 

  14. Kitagawa, W. & Tamura, T. Microbes Environ. 23, 167–171 (2008).

    Article  Google Scholar 

  15. D'Argenio, V. & Salvatore, F. Clin. Chim. Acta 451 Pt A: 97–102 (2015).

    Article  CAS  Google Scholar 

  16. Sham, L.T. et al. Science 345, 220–222 (2014).

    Article  CAS  Google Scholar 

  17. Sewell, E.W. & Brown, E.D. J. Antibiot. 67, 43–51 (2014).

    Article  CAS  Google Scholar 

  18. Lee, S.H. et al. Sci. Transl. Med. 8, 329ra332 (2016).

    Article  Google Scholar 

  19. Huber, J. et al. Chem. Biol. 16, 837–848 (2009).

    Article  CAS  Google Scholar 

  20. Kraal, L., Abubucker, S., Kota, K., Fischbach, M.A. & Mitreva, M. PLoS One 9, e97279 (2014).

    Article  Google Scholar 

  21. Rasmussen, T.T., Kirkeby, L.P., Poulsen, K., Reinholdt, J. & Kilian, M. APMIS 108, 663–675 (2000).

    Article  CAS  Google Scholar 

  22. Graham, J.E. et al. Invest. Ophthalmol. Vis. Sci. 48, 5616–5623 (2007).

    Article  Google Scholar 

  23. Lepage, P. et al. Gastroenterology 141, 227–236 (2011).

    Article  Google Scholar 

  24. Jostins, L. et al. Nature 491, 119–124 (2012).

    Article  CAS  Google Scholar 

  25. Kohli, R.M., Walsh, C.T. & Burkart, M.D. Nature 418, 658–661 (2002).

    Article  CAS  Google Scholar 

  26. Human Microbiome Project Consortium. Nature 486, 215–221 (2012).

  27. Chen, T. et al. Database (Oxford) 2010, baq013 (2010).

    Article  Google Scholar 

  28. Blin, K. et al. Nucleic Acids Res. 41, W204–W212 (2013).

    Article  Google Scholar 

  29. Wang, S.S. J. Am. Chem. Soc. 95, 1328–1333 (1973).

    Article  CAS  Google Scholar 

  30. Cockerill, F.R. et al. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard—Ninth Edition (Clinical and Laboratory Standards Institute, Wayne, PA, 2012).

  31. Hall, M.J., Middleton, R.F. & Westmacott, D. J. Antimicrob. Chemother. 11, 427–433 (1983).

    Article  CAS  Google Scholar 

  32. Garrison, E. & Marth, G. arXiv https://arxiv.org/abs/1207.3907 (2012).

  33. Corrigan, R.M. & Foster, T.J. Plasmid 61, 126–129 (2009).

    Article  CAS  Google Scholar 

Download references

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

  1. John Chu and Xavier Vila-Farres: These authors contributed equally to this work.

Authors and 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

Authors
  1. John Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xavier Vila-Farres
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daigo Inoyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Melinda Ternei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Louis J Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Emma A Gordon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Boojala Vijay B Reddy
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zachary Charlop-Powers
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Henry A Zebroski
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ricardo Gallardo-Macias
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Mark Jaskowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shruthi Satish
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Steven Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. David S Perlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Joel S Freundlich
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Sean F Brady
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

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

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.2207

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing