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