Co-evolution between colibactin production and resistance is linked to clonal expansions in Escherichia coli

Specific strains of Escherichia coli employ the polyketide synthase island to produce a metabolite called colibactin that is implicated in colorectal tumorigenesis via its genotoxic effect on human DNA. However, the damage to host DNA is essentially collateral from ecological competition during bacterial colonisation, where colibactin is used to displace other gut bacteria. Despite intensive recent research on colibactin and its involvement in tumorigenesis, the evolutionary dynamics related to its production remain poorly characterised. We map evolution of colibactin production in E. coli using a large collection of high-resolution genomes and show that its introduction via a mobile element has induced multiple plasmid-mediated acquisitions of previously unrecognised colibactin immunity genes in non-producing multi-drug resistant lineages. Our study suggests that in E. coli , multi-drug resistance is incompatible with colibactin production due to the unbearable combined fitness costs, supported by colibactin-producing phenotypes remaining susceptible to most classes of antibiotics and thriving in regions with low antimicrobial usage. Consequently, resistant lineages circulating in these regions are under selective pressure to acquire colibactin immunity to compete with the endemic colibactin-producing bacteria during colonisation. Conversely, high antimicrobial usage selects for a colibactin susceptible antimicrobial resistant phenotype as it drives the colibactin-producing E. coli towards extinction. Such a duality of evolutionary strategies to become endemic in a host population structured by varying ecological pressures may hold more generally across bacterial species colonizing the human gut.