Escherichia coli-Derived γ-Lactams and Structurally Related Metabolites Are Produced at the Intersection of Colibactin and Fatty Acid Biosynthesis

Colibactin is a genotoxic hybrid polyketide-nonribosomal peptide that drives colorectal cancer initiation. While clinical data suggest colibactin genotoxicity in vivo is largely caused by the major DNA-cross-linking metabolite, the colibactin locus produces a diverse collection of metabolites with mostly unknown biological activities. Here, we describe 10 new colibactin pathway metabolites (1-10) that are dependent on its alpha-aminomalonyl-carrier protein. The most abundant metabolites, 1 and 2, were isolated and structurally characterized mainly by nuclear magnetic resonance spectroscopy to be gamma-lactam derivatives, and the remaining related structures were inferred via shared biosynthetic logic. Our proposed formation of 1-10, which is supported by stereochemical analysis, invokes cross-talk between colibactin and fatty acid biosynthesis, illuminating further the complexity of this diversity-oriented pathway.

Automated summary

The study identified 10 new metabolites related to the colibactin pathway, with the main metabolites being structurally characterized as gamma-lactam derivatives by nuclear magnetic resonance spectroscopy, shedding light on the complexity of this pathway.