title: Comparative metabolomics and structural characterizations illuminate colibactin pathway-dependent small molecules.
abstract: The gene cluster responsible for synthesis of the unknown molecule "colibactin" has been identified in mutualistic and pathogenic Escherichia coli. The pathway endows its producer with a long-term persistence phenotype in the human bowel, a probiotic activity used in the treatment of ulcerative colitis, and a carcinogenic activity under host inflammatory conditions. To date, functional small molecules from this pathway have not been reported. Here we implemented a comparative metabolomics and targeted structural network analyses approach to identify a catalog of small molecules dependent on the colibactin pathway from the meningitis isolate E. coli IHE3034 and the probiotic E. coli Nissle 1917. The structures of 10 pathway-dependent small molecules are proposed based on structural characterizations and network relationships. The network will provide a roadmap for the structural and functional elucidation of a variety of other small molecules encoded by the pathway. From the characterized small molecule set, in vitro bacterial growth inhibitory and mammalian CNS receptor antagonist activities are presented.
authors.affiliation: Department of Chemistry, Yale University , New Haven, Connecticut 06520, United States.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Vizcaino
authors.forename: Philipp
authors.initials: P
authors.lastname: Engel
authors.forename: Eric
authors.initials: E
authors.lastname: Trautman
authors.forename: Jason M
authors.initials: JM
authors.lastname: Crawford
mesh_terms: D000465:Algorithms; D001412:Bacillus subtilis / Q000187:drug effects; D018492:Dopamine Antagonists / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004926:Escherichia coli / Q000302:isolation & purification / Q000378:metabolism* / Q000472:pathogenicity; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D020814:Meningitis, Escherichia coli / Q000382:microbiology; D053858:Metabolic Networks and Pathways; D055432:Metabolomics / Q000379:methods*; D015394:Molecular Structure; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D061065:Polyketides / Q000378:metabolism*; D019936:Probiotics; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D018492:Dopamine Antagonists; D010455:Peptides; D061065:Polyketides; D054852:Small Molecule Libraries; C569566:colibactin