Colibactin leads to a bacteria-specific mutation pattern and self-inflicted DNA damage.

Colibactin produced primarily by Escherichia coli strains of the B2 phylogroup crosslinks DNA and can promote colon cancer in human hosts. We investigated the toxin's impact on colibactin producers and on bacteria co-cultured with producing cells. Using genome-wide genetic screens and mutation accumulation experiments we uncovered the cellular pathways that mitigate colibactin damage and revealed the specific mutations it induces. We discovered that while colibactin targets A/T rich motifs, as observed in human colon cells, it induces a bacteria-unique mutation pattern. Based on this pattern, we predicted that long-term colibactin exposure will culminate in a genomic bias in trinucleotide composition. We tested this prediction by analyzing thousands of E. coli genomes and found that colibactin-producing strains indeed show the predicted skewness in trinucleotide composition. Our work revealed a bacteria-specific mutation pattern and suggests that the resistance protein encoded on the colibactin pathogenicity island is insufficient in preventing self-inflicted DNA damage.