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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Bacillus subtilis / drug effects
  • Dopamine Antagonists / pharmacology
  • Drug Evaluation, Preclinical / methods
  • Escherichia coli / isolation & purification
  • Escherichia coli / metabolism*
  • Escherichia coli / pathogenicity
  • HeLa Cells / drug effects
  • Humans
  • Magnetic Resonance Spectroscopy
  • Meningitis, Escherichia coli / microbiology
  • Metabolic Networks and Pathways
  • Metabolomics / methods*
  • Molecular Structure
  • Peptides / genetics
  • Peptides / metabolism*
  • Polyketides / metabolism*
  • Probiotics
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / metabolism*
  • Small Molecule Libraries / pharmacology


  • Dopamine Antagonists
  • Peptides
  • Polyketides
  • Small Molecule Libraries
  • colibactin