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

Abstract

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 α-aminomalonyl-carrier protein. The most abundant metabolites, 1 and 2, were isolated and structurally characterized mainly by nuclear magnetic resonance spectroscopy to be γ-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.

A commensal-encoded genotoxin drives restriction of Vibrio cholerae colonization and host gut microbiome remodeling

“…We also observed several other characteristic colibactin BGC metabolites characterized previously ( 22 , 26 – 28 ). It should be noted that proteins encoded in the colibactin BGC are involved in the biosynthesis of other metabolites that are potentially bioactive ( 29 , 30 ). However, both clbN and clbL mutants were deficient for killing Vibrio , suggesting that EMS1 produces classical colibactin that directly antagonizes Vibrio .…”

Biosynthesis and bioactivities of microbial genotoxin colibactins

“…For instance, ClbA is involved in the biosynthesis of yersiniabactin, 102 and AM-ACP-ClbE cooperates with fatty acid biosynthesis enzymes to generate g-lactam derivatives. 103 These results indicate that the clb NRPS/PKS assembly line tends to be exible, similar to the thalassospiramide biosynthesis gene cluster, 104,105 and can synthesise various metabolites in vivo.…”