A genetics-free method for high-throughput discovery of cryptic microbial metabolites

Fei Xu, Yihan Wu, Chen Zhang, Katherine M. Davis, Kyuho Moon, Leah B. Bushin, Mohammad R. Seyedsayamdost

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)161-168
Number of pages8
JournalNature Chemical Biology
Volume15
Issue number2
DOIs
StatePublished - Feb 1 2019

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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