|Title||Macrocyclic colibactin induces DNA double-strand breaks via copper-mediated oxidative cleavage|
|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Li Z.R, Li J., Cai W.L, Lai J.YH, McKinnie S.MK, Zhang W.P, Moore BS, Zhang W.J, Qian PY|
|Type of Article||Article|
|Keywords||activation; biosynthesis; bleomycin; chemistry; Damage; health; human microbiome; in-vivo; insights; mechanism; repair|
Colibactin is an assumed human gut bacterial genotoxin, whose biosynthesis is linked to the clb genomic island that has a widespread distribution in pathogenic and commensal human enterobacteria. Colibactin-producing gut microbes promote colon tumour formation and enhance the progression of colorectal cancer via cellular senescence and death induced by DNA doublestrand breaks (DSBs); however, the chemical basis that contributes to the pathogenesis at the molecular level has not been fully characterized. Here, we report the discovery of colibactin-645, a macrocyclic colibactin metabolite that recapitulates the previously assumed genotoxicity and cytotoxicity. Colibactin-645 shows strong DNA DSB activity in vitro and in human cell cultures via a unique copper-mediated oxidative mechanism. We also delineate a complete biosynthetic model for colibactin-645, which highlights a unique fate of the aminomalonate-building monomer in forming the C-terminal 5-hydroxy-4-oxazolecarboxylic acid moiety through the activities of both the polyketide synthase CIbO and the amidase CIbL. This work thus provides a molecular basis for colibactin's DNA DSB activity and facilitates further mechanistic study of colibactin-related colorectal cancer incidence and prevention.