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

  • Nat Chem Biol. 2016 Dec;12(12):1004-1006. doi: 10.1038/nchembio.2207.
John Chu  1 ,  Xavier Vila-Farres  1 ,  Daigo Inoyama  2 ,  Melinda Ternei  1 ,  Louis J Cohen  1 ,  Emma A Gordon  1 ,  Boojala Vijay B Reddy  1 ,  Zachary Charlop-Powers  1 ,  Henry A Zebroski  3 ,  Ricardo Gallardo-Macias  2 ,  Mark Jaskowski  2 ,  Shruthi Satish  2 ,  Steven Park  4 ,  David S Perlin  4 ,  Joel S Freundlich  2 ,  Sean F Brady  1
Affiliations
  • 1. Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, New York, New York, USA.
  • 2. Department of Pharmacology, Physiology, and Neuroscience, Rutgers University-New Jersey Medical School, Newark, New Jersey, USA.
  • 3. Proteomics Resource Center, The Rockefeller University, New York, New York, USA.
  • 4. Public Health Research Institute, Rutgers University-New Jersey Medical School, Newark, New Jersey, USA.
PMID: 27748750 DOI: 10.1038/nchembio.2207
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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