Antony Cougnoux1, Julien Delmas2, Lucie Gibold2, Tiphanie Faïs1, Chiara Romagnoli3, Frederic Robin2, Gabriel Cuevas-Ramos4, Eric Oswald5, Arlette Darfeuille-Michaud6, Fabio Prati3, Guillaume Dalmasso1, Richard Bonnet2. 1. Clermont Université, Université d'Auvergne; Inserm U1071; INRA USC2018, Clermont-Ferrand, France. 2. Clermont Université, Université d'Auvergne; Inserm U1071; INRA USC2018, Clermont-Ferrand, France Centre Hospitalier Universitaire, Clermont-Ferrand, France. 3. Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy. 4. INRA; USC 1360, Université de Toulouse, Toulouse, France Inserm; UMR1043, Université de Toulouse, Toulouse, France CNRS; UMR5282, Université de Toulouse, Toulouse, France. 5. INRA; USC 1360, Université de Toulouse, Toulouse, France Inserm; UMR1043, Université de Toulouse, Toulouse, France CNRS; UMR5282, Université de Toulouse, Toulouse, France UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France CHU Toulouse; Hôpital Purpan; Service de bactériologie-Hygiène, Toulouse, France. 6. Clermont Université, Université d'Auvergne; Inserm U1071; INRA USC2018, Clermont-Ferrand, France Institut Universitaire de Technologie, Université d'Auvergne, Aubière, France.
Abstract
OBJECTIVE: Colorectal cancers (CRCs) are frequently colonised by colibactin toxin-producing Escherichia coli bacteria that induce DNA damage in host cells and exhibit protumoural activities. Our objective was to identify small molecules inhibiting the toxic effects induced by these colibactin-producing bacteria. DESIGN: A structural approach was adopted for the identification of a putative ligand for the ClbP enzyme involved in the synthesis of colibactin. Intestinal epithelial cells and a CRC mouse model were used to assess the activity of the selected compounds in vitro and in vivo. RESULTS: Docking experiments identified two boron-based compounds with computed ligand efficiency values (-0.8 and -0.9 kcal/mol/atom) consistent with data expected for medicinal chemistry leads. The crystalline structure of ClbP in complex with the compounds confirmed that the compounds were binding to the active site of ClbP. The two compounds (2 mM) suppressed the genotoxic activity of colibactin-producing E coli both in vitro and in vivo. The mean degree of suppression of DNA damage for the most efficient compound was 98±2% (95% CI). This compound also prevented cell proliferation and colibactin-producing E coli-induced tumourigenesis in mice. In a CRC murine model colonised by colibactin-producing E coli, the number of tumours decreased by 3.5-fold in animals receiving the compound in drinking water (p<0.01). CONCLUSIONS: These results demonstrate that targeting colibactin production controls the genotoxic and protumoural effects induced by this toxin. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
OBJECTIVE:Colorectal cancers (CRCs) are frequently colonised by colibactin toxin-producing Escherichia coli bacteria that induce DNA damage in host cells and exhibit protumoural activities. Our objective was to identify small molecules inhibiting the toxic effects induced by these colibactin-producing bacteria. DESIGN: A structural approach was adopted for the identification of a putative ligand for the ClbP enzyme involved in the synthesis of colibactin. Intestinal epithelial cells and a CRC mouse model were used to assess the activity of the selected compounds in vitro and in vivo. RESULTS: Docking experiments identified two boron-based compounds with computed ligand efficiency values (-0.8 and -0.9 kcal/mol/atom) consistent with data expected for medicinal chemistry leads. The crystalline structure of ClbP in complex with the compounds confirmed that the compounds were binding to the active site of ClbP. The two compounds (2 mM) suppressed the genotoxic activity of colibactin-producing E coli both in vitro and in vivo. The mean degree of suppression of DNA damage for the most efficient compound was 98±2% (95% CI). This compound also prevented cell proliferation and colibactin-producing E coli-induced tumourigenesis in mice. In a CRC murine model colonised by colibactin-producing E coli, the number of tumours decreased by 3.5-fold in animals receiving the compound in drinking water (p<0.01). CONCLUSIONS: These results demonstrate that targeting colibactin production controls the genotoxic and protumoural effects induced by this toxin. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Entities:
Keywords:
ADJUVANT TREATMENT; BACTERIAL PATHOGENESIS; COLORECTAL CANCER; DRUG DEVELOPMENT; E. COLI
Authors: Hyun Bong Park; Zheng Wei; Joonseok Oh; Hao Xu; Chung Sub Kim; Rurun Wang; Thomas P Wyche; Grazia Piizzi; Richard A Flavell; Jason M Crawford Journal: Nat Microbiol Date: 2020-07-27 Impact factor: 17.745
Authors: Zhongming Ge; Yan Feng; Alexander Sheh; Sureshkumar Muthupalani; Guanyu Gong; Supawadee Chawanthayatham; John M Essigmann; James G Fox Journal: Int J Cancer Date: 2019-05-07 Impact factor: 7.396
Authors: Matthew R Volpe; Matthew R Wilson; Carolyn A Brotherton; Ethan S Winter; Sheila E Johnson; Emily P Balskus Journal: ACS Chem Biol Date: 2019-05-13 Impact factor: 5.100