Aroadmap for natural product discovery based on large-scale genomics and metabolomics

James R. Doroghazi, Jessica C. Albright, Anthony W. Goering, Kou San Ju, Robert R. Haines, Konstantin A. Tchalukov, David P. Labeda, Neil L. Kelleher, William W. Metcalf

Research output: Contribution to journalArticle

231 Scopus citations

Abstract

Actinobacteria encode a wealth of natural product biosynthetic gene clusters, whose systematic study is complicated by numerous repetitive motifs. By combining several metrics, we developed a method for the global classification of these gene clusters into families (GCFs) and analyzed the biosynthetic capacity of Actinobacteria in 830 genome sequences, including 344 obtained for this project. The GCF network, comprising 11,422 gene clusters grouped into 4,122 GCFs, was validated in hundreds of strains by correlating confident mass spectrometric detection of known small molecules with the presence or absence of their established biosynthetic gene clusters. The method also linked previously unassigned GCFs to known natural products, an approach that will enable de novo, bioassay-free discovery of new natural products using large data sets. Extrapolation from the 830-genome data set reveals that Actinobacteria encode hundreds of thousands of future drug leads, and the strong correlation between phylogeny and GCFs frames a roadmap to efficiently access them.

Original languageEnglish (US)
Pages (from-to)963-968
Number of pages6
JournalNature Chemical Biology
Volume10
Issue number11
DOIs
StatePublished - Nov 1 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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