<i>Escherichia coli</i> ClbS is a colibactin resistance protein

<jats:title>Summary</jats:title><jats:p>The genomic <jats:italic>pks</jats:italic> island codes for the biosynthetic machinery that produces colibactin, a peptide‐polyketide metabolite. Colibactin is a genotoxin that contributes to the virulence of extra‐intestinal pathogenic <jats:styled-content style="fixed-case"><jats:italic>E</jats:italic></jats:styled-content><jats:italic>scherichia coli</jats:italic> and promotes colorectal cancer. In this work, we examined whether the <jats:italic>pks</jats:italic>‐encoded <jats:italic>clbS</jats:italic> gene of unknown function could participate in the self‐protection of <jats:styled-content style="fixed-case"><jats:italic>E</jats:italic></jats:styled-content><jats:italic>. coli</jats:italic>‐producing colibactin. A <jats:italic>clb</jats:italic><jats:styled-content style="fixed-case"><jats:italic>S</jats:italic></jats:styled-content> mutant was not impaired in the ability to inflict <jats:styled-content style="fixed-case">DNA</jats:styled-content> damage in <jats:styled-content style="fixed-case">HeL</jats:styled-content>a cells, but the bacteria activated the <jats:styled-content style="fixed-case">SOS</jats:styled-content> response and ceased to replicate. This autotoxicity phenotype was markedly enhanced in a <jats:italic>clb</jats:italic><jats:styled-content style="fixed-case"><jats:italic>S</jats:italic></jats:styled-content> <jats:italic>uvr</jats:italic><jats:styled-content style="fixed-case"><jats:italic>B</jats:italic></jats:styled-content> double mutant inactivated for <jats:styled-content style="fixed-case">DNA</jats:styled-content> repair by nucleotide excision but was suppressed in a <jats:italic>clb</jats:italic><jats:styled-content style="fixed-case"><jats:italic>S</jats:italic></jats:styled-content> <jats:italic>clb</jats:italic><jats:styled-content style="fixed-case"><jats:italic>A</jats:italic></jats:styled-content> double mutant unable to produce colibactin. In addition, ectopic expression of <jats:italic>clb</jats:italic><jats:styled-content style="fixed-case"><jats:italic>S</jats:italic></jats:styled-content> protected infected <jats:styled-content style="fixed-case">HeL</jats:styled-content>a cells from colibactin. Thus, <jats:styled-content style="fixed-case">ClbS</jats:styled-content> is a resistance protein blocking the genotoxicity of colibactin both in the procaryotic and the eucaryotic cells.</jats:p>