Chemistry:Colibactin
Colibactin is a genotoxic metabolite produced by Escherichia coli and other Enterobacteriaceae. Colibactin is a polyketide peptide that can form inter-strand crosslinks in DNA.[1] Colibactin forms DNA inter-strand cross-links by alkylation of adenine moieties on opposing DNA strands.[2] It induces lytic development in certain bacteria that contain prophages.[3] Colibactin is only produced by bacterial strains containing a polyketide synthase genomic island (pks)[4] or clb biosynthetic gene cluster.[2] About 20% of humans in high-income countries are colonized with E. coli that harbor the pks island.[5][6]
Role in cancer
Colibactin is believed to cause mutations leading to colorectal cancer and the progression of colorectal cancer,[4][7][2] especially in early-onset colorectal cancers.[8] Colibactin has been previously demonstrated to have a characteristic mutational signature due to its distinct mechanism.[9] The same mutational signature has been discovered in several cohorts of colon cancer patients, and in smaller numbers of patients with urogenital and head and neck cancers. In urogenital cancers, colibactin exposure has been shown to increase mutational burden in benign cells.[10] Colibactin exposure has been further linked to a proportion of adenomatous polyposis coli (APC) driver insertion-deletions (indels).[8]
References
- ↑ "Isolation of New Colibactin Metabolites from Wild-Type Escherichia coli and In Situ Trapping of a Mature Colibactin Derivative". Journal of the American Chemical Society 143 (14): 5526–5533. 2021. doi:10.1021/jacs.1c01495. PMID 33787233. Bibcode: 2021JAChS.143.5526Z.
- ↑ 2.0 2.1 2.2 "Structure and bioactivity of colibactin". Bioorganic & Medicinal Chemistry Letters 30 (15). 2020. doi:10.1016/j.bmcl.2020.127280. PMID 32527463.
- ↑ Silpe, Justin E.; Wong, Joel W. H.; Owen, Siân V.; Baym, Michael; Balskus, Emily P. (2022-02-23). "The bacterial toxin colibactin triggers prophage induction" (in en). Nature 603 (7900): 315–320. doi:10.1038/s41586-022-04444-3. ISSN 1476-4687. PMID 35197633. Bibcode: 2022Natur.603..315S.
- ↑ 4.0 4.1 Arthur JC (2020). "Microbiota and colorectal cancer: colibactin makes its mark". Nature Reviews Gastroenterology & Hepatology 17 (6): 317–318. doi:10.1038/s41575-020-0303-y. PMID 32317778.
- ↑ "Colibactin: understanding an elusive gut bacterial genotoxin". Natural Product Reports 32 (11): 1534–40. 2015. doi:10.1039/c5np00091b. PMID 26390983.
- ↑ "Geographical variation in the incidence of colorectal cancer and urinary tract cancer is associated with population exposure to colibactin-producing Escherichia coli". The Lancet Microbe 6 (5). 2024. doi:10.1016/j.lanmic.2024.101015. PMID 39644909.
- ↑ "The microbiome, cancer, and cancer therapy". Nature Medicine 25 (3): 377–388. 2019. doi:10.1038/s41591-019-0377-7. PMID 30842679. Bibcode: 2019NatMe..25..377H.
- ↑ 8.0 8.1 Díaz-Gay, Marcos; dos Santos, Wellington; Moody, Sarah; Kazachkova, Mariya; Abbasi, Ammal; Steele, Christopher D.; Vangara, Raviteja; Senkin, Sergey et al. (23 April 2025). "Geographic and age variations in mutational processes in colorectal cancer". Nature 643 (8070): 230–240. doi:10.1038/s41586-025-09025-8. PMID 40267983. Bibcode: 2025Natur.643..230D.
- ↑ Pleguezuelos-Manzano, Cayetano; Puschhof, Jens; Rosendahl Huber, Axel; van Hoeck, Arne; Wood, Henry M.; Nomburg, Jason; Gurjao, Carino; Manders, Freek et al. (April 2020). "Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli" (in en). Nature 580 (7802): 269–273. doi:10.1038/s41586-020-2080-8. ISSN 1476-4687. PMID 32106218.
- ↑ Agrawal, Raag; Al-Hiyari, Sarah; Hugh-White, Rupert; Hromas, Robert; Patel, Yash; Williamson, Elizabeth A.; Mootor, Mohammed F. E.; Gonzalez, Alfredo et al. (2025-06-01). "Colibactin Exerts Androgen-dependent and -independent Effects on Prostate Cancer". European Urology Oncology 8 (3): 716–730. doi:10.1016/j.euo.2024.10.015. ISSN 2588-9311. PMID 39547899. PMC 12075626. https://www.sciencedirect.com/science/article/pii/S2588931124002451.
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