Gut Symbionts from Distinct Hosts Exhibit Genotoxic Activity via Divergent Colibactin Biosynthesis Pathways
ABSTRACTSecondary metabolites produced by nonribosomal peptide synthetase (NRPS) or polyketide synthase (PKS) pathways are chemical mediators of microbial interactions in diverse environments. However, little is known about their distribution, evolution, and functional roles in bacterial symbionts associated with animals. A prominent example is colibactin, a largely unknown family of secondary metabolites produced byEscherichia colivia a hybrid NRPS-PKS biosynthetic pathway that inflicts DNA damage upon eukaryotic cells and contributes to colorectal cancer and tumor formation in the mammalian gut. Thus far, homologs of this pathway have only been found in closely relatedEnterobacteriaceae, while a divergent variant of this gene cluster was recently discovered in a marine alphaproteobacterialPseudovibriostrain. Herein, we sequenced the genome ofFrischella perraraPEB0191, a bacterial gut symbiont of honey bees and identified a homologous colibactin biosynthetic pathway related to those found inEnterobacteriaceae. We show that the colibactin genomic island (GI) has conserved gene synteny and biosynthetic module architecture acrossF. perrara,Enterobacteriaceae, and thePseudovibriostrain. Comparative metabolomics analyses ofF. perraraandE. colifurther reveal that these two bacteria produce related colibactin pathway-dependent metabolites. Finally, we demonstrate thatF. perrara, likeE. coli, causes DNA damage in eukaryotic cellsin vitroin a colibactin pathway-dependent manner. Together, these results support that divergent variants of the colibactin biosynthetic pathway are widely distributed among bacterial symbionts, producing related secondary metabolites and likely endowing its producer with functional capabilities important for diverse symbiotic associations.