title: The colibactin warhead crosslinks DNA.
abstract: Members of the human microbiota are increasingly being correlated to human health and disease states, but the majority of the underlying microbial metabolites that regulate host-microbe interactions remain largely unexplored. Select strains of Escherichia coli present in the human colon have been linked to the initiation of inflammation-induced colorectal cancer through an unknown small-molecule-mediated process. The responsible non-ribosomal peptide-polyketide hybrid pathway encodes 'colibactin', which belongs to a largely uncharacterized family of small molecules. Genotoxic small molecules from this pathway that are capable of initiating cancer formation have remained elusive due to their high instability. Guided by metabolomic analyses, here we employ a combination of NMR spectroscopy and bioinformatics-guided isotopic labelling studies to characterize the colibactin warhead, an unprecedented substituted spirobicyclic structure. The warhead crosslinks duplex DNA in vitro, providing direct experimental evidence for colibactin's DNA-damaging activity. The data support unexpected models for both colibactin biosynthesis and its mode of action.
authors.affiliation: 1] Department of Chemistry, Yale University, New Haven, Connecticut 06510, USA [2] Chemical Biology Institute, Yale University, West Haven, Connecticut 06516, USA.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Vizcaino
authors.affiliation: 1] Department of Chemistry, Yale University, New Haven, Connecticut 06510, USA [2] Chemical Biology Institute, Yale University, West Haven, Connecticut 06516, USA [3] Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, Connecticut 06536, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Crawford
mesh_terms: D003106:Colon / Q000382:microbiology; D004247:DNA / Q000737:chemistry*; D004926:Escherichia coli / Q000737:chemistry; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000737:chemistry*; D061065:Polyketides / Q000737:chemistry*; D011487:Protein Conformation
chemical_list: D010455:Peptides; D061065:Polyketides; C569566:colibactin; D004247:DNA