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

Colibactin, a metabolite produced by gut bacteria carrying the polyketide synthase (pks) island, is associated with host genotoxicity and tumorigenesis. However, no FDA-approved therapeutics target colibactin. Here, we demonstrate that expression of the intracellular colibactin self-resistance protein (ClbS) on the surface of engineered bacteria shield the host from the genotoxic effects across multiple pks+ isolates. The surface display, due to 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 mouse model of colitis and suppressed tumorigenesis in mouse models of colon cancer caused by pks+ E. coli. Our results demonstrate the feasibility of inhibiting bacterial genotoxins in the gut establishing a starting point for therapeutics targeting other potential cancer-causing bacterial metabolites.