Select strains of Escherichia coli and Klebsiella pneumoniae produce the virulence factor and cytotoxin known as colibactin. Colibactin is derived from its prodrug form known as precolibactin. Pathogenic strains of adherent invasive E. coli (AIEC) carrying the colibactin pathway (clb+) cause tumor formation in at least four distinct mouse models examined to date and are thought to be responsible for initiating colorectal cancer in humans. Through a combination of genome editing, stable isotope labeling, DNA alkylation, and chemical synthesis studies, we characterized the structures of precolibactin, colibactin, and its DNA interstrand crosslink product from DNA exposed to clb+ E. coli. The structure of colibactin was confirmed by comparison to a synthetic standard. The standard led to an identical DNA interstrand crosslink as the natural materials. An uncharacterized peptidase ClbL represented the final critical step in precolibactin biosynthesis was responsible for converting DNA alkylators into DNA interstrand crosslinkers. These studies present the structure, mode of action, and biosynthesis of (pre)colibactins that account for all known biosynthesis and cancer cell biology studies for this important pathway.

Structure elucidation of colibactin and its DNA interstrand cross-link product

2019 Fall National Meeting

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