Comparative
Metabolomics and Structural Characterizations
Illuminate Colibactin Pathway-Dependent Small Molecules
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Abstract
The
gene cluster responsible for synthesis of the unknown molecule
“colibactin” has been identified in mutualistic and
pathogenic Escherichia coli. The pathway
endows its producer with a long-term persistence phenotype in the
human bowel, a probiotic activity used in the treatment of ulcerative
colitis, and a carcinogenic activity under host inflammatory conditions.
To date, functional small molecules from this pathway have not been
reported. Here we implemented a comparative metabolomics and targeted
structural network analyses approach to identify a catalog of small
molecules dependent on the colibactin pathway from the meningitis
isolate E. coli IHE3034 and the probiotic E. coli Nissle 1917. The structures of 10 pathway-dependent
small molecules are proposed based on structural characterizations
and network relationships. The network will provide a roadmap for
the structural and functional elucidation of a variety of other small
molecules encoded by the pathway. From the characterized small molecule
set, <i>in vitro</i> bacterial growth inhibitory and mammalian
CNS receptor antagonist activities are presented