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
2016 ACS Central Science  
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
more » ... w 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.
doi:10.1021/acscentsci.5b00331 pmid:27163034 pmcid:PMC4827660 fatcat:zzvi5qauarcblgbpbwpik6moom