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.
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