Colibactin

Colibactin is a family of secondary metabolites produced by certain Escherichia coli and related Enterobacteriaceae, encoded by the pks genomic island. It functions as a genotoxin that damages DNA in host cells.

Biosynthesis: The pks island encodes a hybrid polyketide synthase–nonribosomal peptide synthetase (PKS-NRPS) assembly line that constructs precolibactins. A dedicated ClbP peptidase activates these compounds by cleaving side chains to generate the mature colibactin, which is highly reactive but unstable. The exact structure of mature colibactin has remained elusive, so researchers rely on studies of intermediates, gene function, and indirect activity to understand its chemistry.

Mechanism: Colibactin exposure causes DNA alkylation and interstrand cross-linking, leading to replication stress and double-strand breaks in eukaryotic cells; DNA damage responses such as γ-H2AX foci are observed in cell culture, and some animal studies report related genomic instability.

Biological and clinical relevance: pks-positive bacteria have been associated with colorectal tumorigenesis in experimental models, and pks DNA sequences have been found in some human colorectal cancers. Nonetheless, direct causation in humans remains unproven, and colibactin-producing commensals (including some probiotic strains) complicate risk assessment.

Detection and status: The instability of mature colibactin hinders isolation of the molecule; most evidence comes from genetic, biochemical, and indirect chemical assays, including detection of specific DNA adducts and cross-links and profiling of the clb gene cluster.