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. Epub 2016 Oct 17.

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.

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / isolation & purification*
  • Anti-Bacterial Agents / pharmacology*
  • Biological Products / chemical synthesis
  • Biological Products / chemistry
  • Biological Products / isolation & purification*
  • Biological Products / pharmacology*
  • Drug Discovery / methods*
  • Humans
  • Lipopeptides / chemical synthesis
  • Lipopeptides / chemistry
  • Lipopeptides / genetics
  • Lipopeptides / pharmacology
  • Methicillin-Resistant Staphylococcus aureus / drug effects*
  • Methicillin-Resistant Staphylococcus aureus / enzymology
  • Microbial Sensitivity Tests
  • Microbiota / genetics*
  • Molecular Conformation
  • Peptide Synthases / genetics
  • beta-Lactams / agonists
  • beta-Lactams / metabolism

Substances

  • Anti-Bacterial Agents
  • Biological Products
  • Lipopeptides
  • beta-Lactams
  • humimycin A
  • humimycin B
  • Peptide Synthases
  • non-ribosomal peptide synthase

Associated data

  • PubChem-Substance/318018254
  • PubChem-Substance/318018255