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 pksisolates. 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 pksE. 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.