title: Metabologenomics: Correlation of Microbial Gene Clusters with Metabolites Drives Discovery of a Nonribosomal Peptide with an Unusual Amino Acid Monomer.
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.
authors.affiliation: Departments of Chemistry, Molecular Biosciences, and the Feinberg School of Medicine, Northwestern University , Evanston, Illinois 60208, United States.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Goering
authors.affiliation: Departments of Chemistry, Molecular Biosciences, and the Feinberg School of Medicine, Northwestern University , Evanston, Illinois 60208, United States.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: McClure
authors.affiliation: Department of Microbiology and the Carl R. Woese Institute of Genomic Biology, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
authors.forename: James R
authors.initials: JR
authors.lastname: Doroghazi
authors.affiliation: Departments of Chemistry, Molecular Biosciences, and the Feinberg School of Medicine, Northwestern University , Evanston, Illinois 60208, United States.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Albright
authors.affiliation: Departments of Chemistry, Molecular Biosciences, and the Feinberg School of Medicine, Northwestern University , Evanston, Illinois 60208, United States.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Haverland
authors.affiliation: Integrated Molecular Structure Education and Research Center, Weinberg College of Arts and Sciences, Northwestern University , Evanston, Illinois 60208, United States.
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and the Carl R. Woese Institute of Genomic Biology, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
authors.forename: Kou-San
authors.initials: KS
authors.lastname: Ju
authors.affiliation: Departments of Chemistry, Molecular Biosciences, and the Feinberg School of Medicine, Northwestern University , Evanston, Illinois 60208, United States.
authors.forename: Regan J
authors.initials: RJ
authors.lastname: Thomson
authors.affiliation: Department of Microbiology and the Carl R. Woese Institute of Genomic Biology, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
authors.forename: William W
authors.initials: WW
authors.lastname: Metcalf
authors.affiliation: Departments of Chemistry, Molecular Biosciences, and the Feinberg School of Medicine, Northwestern University , Evanston, Illinois 60208, United States.
authors.forename: Neil L
authors.initials: NL
authors.lastname: Kelleher