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Colibactin

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Colibactin
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
  • 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") believed to cause mutations leading to colorectal cancer and the progression of colorectal cancer,[1][2][3][4] especially in early-onset colorectal cancers.[5] Colibactin is a polyketide peptide that can form interstrand crosslinks in DNA.[2] Colibactin is only produced by bacterial strains containing a polyketide synthase genomic island (pks)[1] or clb biosynthetic gene cluster.[4] About 20% of humans in high-income countries are colonized with E. coli that harbor the pks island.[6][7]

Colibactin forms DNA inter-strand cross-links by alkylation of adenine moieties on opposing DNA strands.[4] It induces lytic development in certain bacteria that contain prophages.[8] Colibactin has been previously demonstrated to have a characteristic mutational signature.[9] The same mutational signature was discovered in several cohorts of colon cancer patients, and in smaller numbers of patients with urogenital and head and neck cancers. Colibactin exposure has been further linked to a proportion of APC driver indels.[5]

References

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  1. ^ a b 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.
  2. ^ a b 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.
  3. ^ 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.
  4. ^ a b c 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.
  5. ^ a b 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. PMID 40267983. Retrieved 23 April 2025.
  6. ^ Balskus EP (2015). "Colibactin: understanding an elusive gut bacterial genotoxin". Natural Product Reports. 32 (11): 1534–40. doi:10.1039/c5np00091b. PMID 26390983.
  7. ^ 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.
  8. ^ 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.
  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.
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