Jean-Philippe Nougayrède and colleagues began the search for a new toxin after observing that transient infection with certain E. coli isolates — some commensal and extraintestinal pathogenic isolates but no laboratory or intestinal pathogenic strains — induced marked morphological changes in cultured eukaryotic cells. This cytopathic effect, comprising gradual cell and nuclear enlargement and a block in cell division, was contact dependent, but internalization of the bacteria was not required. This suggested a role for a toxin, but none of the known E. coli 'cyclomodulins' — cytolethal distending toxin, cytotoxic necrotizing factor or cycle inhibiting factor — was found to be involved.
Further work using transposon mutagenesis identified a 54-kb genomic island that was necessary for the cytopathic effect. The island was named the pks island as it carries the machinery necessary for the synthesis of hybrid polyketide–peptide compounds, comprising the genes encoding three non-ribosomal peptide synthases (NRPSs), three polyketide synthases (PKSs), two hybrid NRPS–PKS compounds and nine accessory enzymes. Mutagenesis studies revealed that all of the enzymes encoded on the pks island were essential for the cytopathic effect, apart from one of the accessory enzymes. Investigations of the mode of action found that it prevented eukaryotic cell division by inducing cell-cycle arrest and activating the G2 checkpoint. Moreover, analysis of the effects of the exposure of E. coli carrying the pks island on a DNA-damage marker demonstrated that the presence of the island was associated with the accumulation of double-strand DNA breaks (DSBs), and so has genotoxic activity.
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