A genetics-free method for high-throughput discovery of cryptic microbial metabolites. Author Fei Xu, Yihan Wu, Chen Zhang, Katherine Davis, Kyuho Moon, Leah Bushin, Mohammad Seyedsayamdost Publication Year 2019 Type Journal Article Abstract Bacteria contain an immense untapped trove of novel secondary metabolites in the form of 'silent' biosynthetic gene clusters (BGCs). These can be identified bioinformatically but are not expressed under normal laboratory growth conditions. Methods to access their products would dramatically expand the pool of bioactive compounds. We report a universal high-throughput method for activating silent BGCs in diverse microorganisms. Our approach relies on elicitor screening to induce the secondary metabolome of a given strain and imaging mass spectrometry to visualize the resulting metabolomes in response to ~500 conditions. Because it does not require challenging genetic, cloning, or culturing procedures, this method can be used with both sequenced and unsequenced bacteria. We demonstrate the power of the approach by applying it to diverse bacteria and report the discovery of nine cryptic metabolites with potentially therapeutic bioactivities, including a new glycopeptide chemotype with potent inhibitory activity against a pathogenic virus. Keywords Bacteria, High-Throughput Screening Assays, Mass Spectrometry, Multigene Family, Metabolomics, Biological Products, Biosynthetic Pathways, Metabolome Journal Nat Chem Biol Volume 15 Issue 2 Pages 161-168 Date Published 2019 Feb ISSN Number 1552-4469 DOI 10.1038/s41589-018-0193-2 Alternate Journal Nat Chem Biol PMCID PMC6339573 PMID 30617293 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML