Fig. 4. Colibactin is a microbial risk factor for colorectal cancer.

a) The colibactin biosynthetic gene cluster encodes for the production of predicted mature precolibactin 1491. The colibactin gene cluster contains 19 genes that encode three polyketide synthases (PKSs), three nonribosomal peptide synthetases (NRPSs), two hybrid PKS/NRPS systems, and 11 tailoring and accessory proteins. Amino acid, acyl- and malonyl-CoA building blocks are selected and loaded onto the enzymatic modules to produce precolibactin. Amidase ClbL promotes heterodimerization to generate a proposed asymmetric structure precolibactin 1491. b) Precolibactins are transported into the periplasm before being cleaved by peptidase ClbP to release a dual-warhead metabolite, which can undergo further cyclizations. ClbP peptidase activation can be blocked by inhibitors featuring a boronic acid motif. Colibactin(s) traffic to host cell nuclei by an unknown mechanism, indicated by ‘?’. c) Colibactin electrophilic spirocyclopropane moieties can cross-link DNA. Additional electrophilic sites of colibactin have the potential for additional unexplored reactions such as addition at the C4 of the lactam ring or addition at the central dicarbonyl spacer separating the two warhead motifs. Crosslinking leads to double-stranded DNA breaks, which contribute to colorectal cancer risk through increased cell proliferation, inflammation, and senescence. Part b and c are adapted from ref.²⁰⁰, Springer Nature Limited.