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The colibactin warhead crosslinks DNA

Maria I Vizcaino1, Jason M Crawford2

  • 11] Department of Chemistry, Yale University, New Haven, Connecticut 06510, USA [2] Chemical Biology Institute, Yale University, West Haven, Connecticut 06516, USA.

Nature Chemistry
|April 23, 2015
PubMed

Insights

Researchers identified the unstable, DNA-damaging colibactin warhead from Escherichia coli. This finding advances understanding of how gut bacteria contribute to colorectal cancer initiation via small molecules.

Area of Science:

  • Microbiology and Molecular Biology
  • Cancer Research
  • Metabolomics

Background:

  • Human microbiota metabolites are crucial for host-microbe interactions but remain largely uncharacterized.
  • Certain Escherichia coli strains are linked to inflammation-induced colorectal cancer via unknown small molecules.
  • Colibactin, produced by a non-ribosomal peptide-polyketide hybrid pathway, is implicated but its genotoxic small molecules are unstable and elusive.

Purpose of the Study:

  • To characterize the unstable, genotoxic small molecule responsible for DNA damage and cancer initiation by specific Escherichia coli strains.
  • To elucidate the structure of the colibactin warhead, a key component in the cancer-promoting pathway.

Main Methods:

  • Utilized metabolomic analyses to guide the research.
  • Employed Nuclear Magnetic Resonance (NMR) spectroscopy for structural determination.
  • Conducted bioinformatics-guided isotopic labeling studies.

Main Results:

  • Characterized the colibactin warhead as an unprecedented substituted spirobicyclic structure.
  • Demonstrated that the colibactin warhead crosslinks duplex DNA in vitro.
  • Provided direct experimental evidence for colibactin's DNA-damaging activity.

Conclusions:

  • The identified colibactin warhead structure provides a molecular basis for its genotoxicity.
  • The findings support novel models for both colibactin biosynthesis and its mechanism of action in promoting cancer.
  • This research deepens the understanding of microbial metabolites in human health and disease, specifically colorectal cancer.

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