The human gut bacterial genotoxin colibactin alkylates DNA

Abstract

Bacterial warhead targets DNA The bacterial toxin colibactin causes double-stranded DNA breaks and is associated with the occurrence of bacterially induced colorectal cancer in humans. However, isolation of colibactin is difficult, and its mode of action is poorly understood. Wilson et al. studied Escherichia coli that contain the biosynthetic gene island called pks , which is associated with colibactin production (see the Perspective by Bleich and Arthur). They identified the DNA adducts that resulted from incubating pks + E. coli in human cells. To overcome the lack of colibactin for direct analysis, mimics of the pks product were synthesized. From the resulting synthetic adenine-colibactin adducts, it became evident that alkylation via a cyclopropane “warhead” breaks the DNA strands. Similar DNA adducts were then identified in the gut epithelia of mice infected with pks + E. coli. Science , this issue p. eaar7785 ; see also p. 689