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2015 ; 7
(5
): 411-7
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The colibactin warhead crosslinks DNA
#MMPMID25901819
Vizcaino MI
; Crawford JM
Nat Chem
2015[May]; 7
(5
): 411-7
PMID25901819
show ga
Members of the human microbiota are increasingly being correlated to human health
and disease states, but the majority of the underlying microbial metabolites that
regulate host-microbe interactions remain largely unexplored. Select strains of
Escherichia coli present in the human colon have been linked to the initiation of
inflammation-induced colorectal cancer through an unknown small-molecule-mediated
process. The responsible non-ribosomal peptide-polyketide hybrid pathway encodes
'colibactin', which belongs to a largely uncharacterized family of small
molecules. Genotoxic small molecules from this pathway that are capable of
initiating cancer formation have remained elusive due to their high instability.
Guided by metabolomic analyses, here we employ a combination of NMR spectroscopy
and bioinformatics-guided isotopic labelling studies to characterize the
colibactin warhead, an unprecedented substituted spirobicyclic structure. The
warhead crosslinks duplex DNA in vitro, providing direct experimental evidence
for colibactin's DNA-damaging activity. The data support unexpected models for
both colibactin biosynthesis and its mode of action.
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