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

• Published in: Nature chemical biology Vol. 12; no. 12; pp. 1004 - 1006
• Main Authors: Chu, John, Vila-Farres, Xavier, Inoyama, Daigo, Ternei, Melinda, Cohen, Louis J, Gordon, Emma A, Reddy, Boojala Vijay B, Charlop-Powers, Zachary, Zebroski, Henry A, Gallardo-Macias, Ricardo, Jaskowski, Mark, Satish, Shruthi, Park, Steven, Perlin, David S, Freundlich, Joel S, Brady, Sean F
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2016; Nature Publishing Group
• Subjects: 631/326/41; 631/92/349; 631/92/60; 631/92/611; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - isolation & purification; Anti-Bacterial Agents - pharmacology; Antibiotics; Bacteria; beta-Lactams - agonists; beta-Lactams - metabolism; Biochemical Engineering; Biochemistry; Biological Products - chemical synthesis; Biological Products - chemistry; Biological Products - isolation & purification; Biological Products - pharmacology; Bioorganic Chemistry; brief-communication; Cell Biology; Chemical synthesis; Chemistry; Chemistry/Food Science; 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; Natural products; Peptide Synthases - genetics; Staphylococcus aureus; Staphylococcus infections
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.2207

The synthetic bioinformatic natural products (syn-BNPs) approach identifies putative natural products that are validated directly by independent synthesis. Its application led to the identification of humimycins, non-ribosomal peptides that have antimicrobial activity in mice. 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.