Surface expression of antitoxin on engineered bacteria neutralizes genotoxic colibactin in the gut

ABSTRACT

Colibactin, a metabolite produced by gut bacteria carrying the polyketide synthase (pks) island, is associated with host genotoxicity and tumorigenesis. However, no Food and Drug Administration-approved therapeutics directly target colibactin. Here we show that expression of the intracellular colibactin self-resistance protein (ClbS) on the surface of engineered bacteria shields the host from genotoxic effects across multiple pks+ isolates. The surface display, due to the fusion of ClbS with outer membrane protein A (ClbS-OmpA) in Escherichia coli, effectively reduced colibactin-induced DNA damage and cell cycle arrest in human cell lines and organoids, outperforming D-serine, a small-molecule inhibitor of colibactin synthesis. The engineered strains mitigated intestinal damage in a mouse model of colitis and suppressed tumorigenesis in mouse models of colon cancer caused by pks+ E. coli. Our results show the feasibility of inhibiting bacterial genotoxins in the gut, establishing a starting point for therapeutics targeting other potential cancer-causing bacterial metabolites.