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J Am Chem Soc. 2014 Jul 2;136(26):9244-7. doi: 10.1021/ja503450q. Epub 2014 Jun 20.

Comparative metabolomics and structural characterizations illuminate colibactin pathway-dependent small molecules.

Author information

1
Department of Chemistry, Yale University , New Haven, Connecticut 06520, United States.

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, in vitro bacterial growth inhibitory and mammalian CNS receptor antagonist activities are presented.

PMID:
24932672
PMCID:
PMC4091280
DOI:
10.1021/ja503450q
[Indexed for MEDLINE]
Free PMC Article

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