Colibactin

Last updated
Colibactin
Colibactin.svg
Names
IUPAC name
2-[6-[(2S)-2-methyl-3,4-dihydro-2H-pyrrol-5-yl]-5-oxo-4-azaspiro[2.4]hept-6-en-7-yl]-N-[[4-[2-[4-[2-[[2-[6-[(2S)-2-methyl-3,4-dihydro-2H-pyrrol-5-yl]-5-oxo-4-azaspiro[2.4]hept-6-en-7-yl]acetyl]amino]acetyl]-1,3-thiazol-2-yl]-2-oxoacetyl]-1,3-thiazol-2-yl]methyl]acetamide
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
KEGG
PubChem CID
  • InChI=1S/C37H38N8O7S2/c1-17-3-5-21(40-17)29-19(36(7-8-36)44-33(29)51)11-26(47)38-13-25(46)23-15-54-35(43-23)32(50)31(49)24-16-53-28(42-24)14-39-27(48)12-20-30(22-6-4-18(2)41-22)34(52)45-37(20)9-10-37/h15-18H,3-14H2,1-2H3,(H,38,47)(H,39,48)(H,44,51)(H,45,52)/t17-,18-/m0/s1
    Key: ZWKHDAZPVITMAI-ROUUACIJSA-N
  • C[C@H]1CCC(=N1)C2=C(C3(CC3)NC2=O)CC(=O)NCC4=NC(=CS4)C(=O)C(=O)C5=NC(=CS5)C(=O)CNC(=O)CC6=C(C(=O)NC67CC7)C8=N[C@H](CC8)C
Properties
C37H38N8O7S2
Molar mass 770.88 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Colibactin is a genotoxic metabolite produced by Escherichia coli and other Enterobacteriaceae ("enteric bacteria"). 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]

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, Colibacin 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

  1. ↑ Zhou T, Hirayama Y, Watanabe K (2021). "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. doi:10.1021/jacs.1c01495. PMID   33787233. S2CID   232431632.
  2. 1 2 3 Wernke KM, Xue M, Herzon SB (2020). "Structure and bioactivity of colibactin". Bioorganic & Medicinal Chemistry Letters . 30 (15): 127280. doi:10.1016/j.bmcl.2020.127280. PMC   7309967 . PMID   32527463.
  3. ↑ 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". Nature. 603 (7900): 315–320. Bibcode:2022Natur.603..315S. doi:10.1038/s41586-022-04444-3. ISSN   1476-4687. PMC   8907063 . PMID   35197633.
  4. 1 2 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. S2CID   216033220.
  5. ↑ Balskus EP (2015). "Colibactin: understanding an elusive gut bacterial genotoxin". Natural Product Reports. 32 (11): 1534–40. doi:10.1039/c5np00091b. PMID   26390983.
  6. ↑ Mäklin T, Taira A, Arredondo-Alonso S, Shao Y, Stratton MR, Lawley TD, Aaltonen LA, Corander J (2024). "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. doi: 10.1016/j.lanmic.2024.101015 . PMID   39644909.
  7. ↑ Helmink BA, Khan M, Wargo JA (2019). "The microbiome, cancer, and cancer therapy". Nature Medicine . 25 (3): 377–388. doi:10.1038/s41591-019-0377-7. PMID   30842679. S2CID   71145949.
  8. 1 2 Díaz-Gay, Marcos; dos Santos, Wellington; Moody, Sarah; Kazachkova, Mariya; Abbasi, Ammal; Steele, Christopher D.; Vangara, Raviteja; Senkin, Sergey; Wang, Jingwei; Fitzgerald, Stephen; Bergstrom, Erik N.; Khandekar, Azhar; Otlu, Burçak; Abedi-Ardekani, Behnoush; de Carvalho, Ana Carolina; Cattiaux, Thomas; Penha, Ricardo Cortez Cardoso; Gaborieau, Valérie; Chopard, Priscilia; Carreira, Christine; Cheema, Saamin; Latimer, Calli; Teague, Jon W.; Mukeriya, Anush; Zaridze, David; Cox, Riley; Albert, Monique; Phouthavongsy, Larry; Gallinger, Steven; Malekzadeh, Reza; Niavarani, Ahmadreza; Miladinov, Marko; Erić, Katarina; Milosavljevic, Sasa; Sangrajrang, Suleeporn; Curado, Maria Paula; Aguiar, Samuel; Reis, Rui Manuel; Reis, Monise Tadin; Romagnolo, Luis Gustavo; Guimarães, Denise Peixoto; Holcatova, Ivana; Kalvach, Jaroslav; Vaccaro, Carlos Alberto; Piñero, Tamara Alejandra; Świątkowska, Beata; Lissowska, Jolanta; Roszkowska-Purska, Katarzyna; Huertas-Salgado, Antonio; Shibata, Tatsuhiro; Shiba, Satoshi; Sangkhathat, Surasak; Chitapanarux, Taned; Roshandel, Gholamreza; Ashton-Prolla, Patricia; Damin, Daniel C.; de Oliveira, Francine Hehn; Humphreys, Laura; Lawley, Trevor D.; Perdomo, Sandra; Stratton, Michael R.; Brennan, Paul; Alexandrov, Ludmil B. (23 April 2025). "Geographic and age variations in mutational processes in colorectal cancer" . Nature. doi: 10.1038/s41586-025-09025-8 . PMC   12221974 . PMID   40267983 . Retrieved 23 April 2025.
  9. ↑ Pleguezuelos-Manzano, Cayetano; Puschhof, Jens; Rosendahl Huber, Axel; van Hoeck, Arne; Wood, Henry M.; Nomburg, Jason; Gurjao, Carino; Manders, Freek; Dalmasso, Guillaume; Stege, Paul B.; Paganelli, Fernanda L.; Geurts, Maarten H.; Beumer, Joep; Mizutani, Tomohiro; Miao, Yi (April 2020). "Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli". Nature. 580 (7802): 269–273. doi:10.1038/s41586-020-2080-8. ISSN   1476-4687. PMC   8142898 . PMID   32106218.
  10. ↑ Agrawal, Raag; Al-Hiyari, Sarah; Hugh-White, Rupert; Hromas, Robert; Patel, Yash; Williamson, Elizabeth A.; Mootor, Mohammed F. E.; Gonzalez, Alfredo; Fu, Jianmin; Haas, Roni; Jordan, Madison; Wickes, Brian L.; Mohammed, Ghouse; Tian, Mao; Doris, Molly J. (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.
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