The colibactin warhead crosslinks DNA
Open accessAbstract
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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Stable-isotope precursor feeding has been used to identify natural products with specific biosynthetic precursors such as colibactin and xanthomonic acid, and to investigate the biosynthesis of fungisporin and related analogues.
“several studies have made use of stable-isotope precursor feeding to identify natural products with specific biosynthetic precursors such as colibactin,68 xanthomonic acid69 and to investigate the biosynthesis of fungisporin and the discovery of related analogues.70”
From Connecting metabolome and phenotype: recent advances in functional metabolomics tools for the identification of bioactive natural products (2024) · cites this paper as [68]
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- Authors
- Vizcaino, M. I., & Crawford, J. M.
- Affiliations
- Yale University (US)
- Corresponding author
- Crawford, Jason M.
- ORCID
- Crawford, Jason M.
- Venue
- Nature Chemistry
- Published
- 2015-04-06
- Volume
- 7
- Issue
- 5
- Pages
- 411-417
- ISSN
- 1755-4330 (ISSN-L)
- 1755-4349
- PMC
- PMC4499846
- OpenAlex
- W2003545535
- Cited by
- 247
- References
- 44
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 18 · 2023: 12 · 2022: 15 · 2021: 30 · 2020: 28 · 2019: 29 · 2018: 25 · 2017: 24 · 2016: 30 · 2015: 14
- FWCI
- 22.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Damon Runyon Cancer Research Foundation
- National Institutes of Health
- National Cancer Institute (DP2CA186575)
- Topics
- Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Microbial Metabolism and Applications
- Keywords
- colibactin, DNA cross-linking, DNA damage, nonribosomal peptide synthetase, polyketide synthase, colorectal cancer, Escherichia coli, human gut microbiome, isotopic labeling, metabolomics, genotoxicity
- MeSH terms
- Colon, DNA, Escherichia coli, Humans, Peptides, Protein Conformation, Nuclear Magnetic Resonance, Biomolecular, Polyketides
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