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ACS Cent Sci. 2016 Feb 24;2(2):99-108. doi: 10.1021/acscentsci.5b00331. Epub 2016 Jan 20.

Metabologenomics: Correlation of Microbial Gene Clusters with Metabolites Drives Discovery of a Nonribosomal Peptide with an Unusual Amino Acid Monomer.

Author information

1
Departments of Chemistry, Molecular Biosciences, and the Feinberg School of Medicine, Northwestern University , Evanston, Illinois 60208, United States.
2
Department of Microbiology and the Carl R. Woese Institute of Genomic Biology, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
3
Integrated Molecular Structure Education and Research Center, Weinberg College of Arts and Sciences, Northwestern University , Evanston, Illinois 60208, United States.

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.

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