Metabologenomics: Correlation of microbial gene clusters with metabolites drives discovery of a nonribosomal peptide with an unusual amino acid monomer

Anthony W. Goering, Ryan A. McClure, James R. Doroghazi, Jessica C. Albright, Nicole A. Haverland, Yongbo Zhang, Kou San Ju, Regan J. Thomson, William W. Metcalf, Neil L. Kelleher

Research output: Contribution to journalArticlepeer-review

Abstract

For more than half a century the pharmaceutical industry has sifted through natural products produced by microbes, uncovering new scaffolds and fashioning them into a broad range of vital drugs. We sought a strategy to reinvigorate the discovery of natural products with distinctive structures using bacterial genome sequencing combined with metabolomics. By correlating genetic content from 178 actinomycete genomes with mass spectrometry-enabled analyses of their exported metabolomes, we paired new secondary metabolites with their biosynthetic gene clusters. We report the use of this new approach to isolate and characterize tambromycin, a new chlorinated natural product, composed of several nonstandard amino acid monomeric units, including a unique pyrrolidine-containing amino acid we name tambroline. Tambromycin shows antiproliferative activity against cancerous human B- and T-cell lines. The discovery of tambromycin via large-scale correlation of gene clusters with metabolites (a.k.a. metabologenomics) illuminates a path for structure-based discovery of natural products at a sharply increased rate.

Original languageEnglish (US)
Pages (from-to)99-108
Number of pages10
JournalACS Central Science
Volume2
Issue number2
DOIs
StatePublished - Feb 24 2016

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

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