title: Small-molecule inhibitors prevent the genotoxic and protumoural effects induced by colibactin-producing bacteria.
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.
  
  
  METHODS
  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.
authors.affiliation: Clermont Université, Université d'Auvergne; Inserm U1071; INRA USC2018, Clermont-Ferrand, France.
authors.forename: Antony
authors.initials: A
authors.lastname: Cougnoux
authors.affiliation: Clermont Université, Université d'Auvergne; Inserm U1071; INRA USC2018, Clermont-Ferrand, France Centre Hospitalier Universitaire, Clermont-Ferrand, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Delmas
authors.affiliation: Clermont Université, Université d'Auvergne; Inserm U1071; INRA USC2018, Clermont-Ferrand, France Centre Hospitalier Universitaire, Clermont-Ferrand, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Gibold
authors.affiliation: Clermont Université, Université d'Auvergne; Inserm U1071; INRA USC2018, Clermont-Ferrand, France.
authors.forename: Tiphanie
authors.initials: T
authors.lastname: Faïs
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Romagnoli
authors.affiliation: Clermont Université, Université d'Auvergne; Inserm U1071; INRA USC2018, Clermont-Ferrand, France Centre Hospitalier Universitaire, Clermont-Ferrand, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Robin
authors.affiliation: INRA; USC 1360, Université de Toulouse, Toulouse, France Inserm; UMR1043, Université de Toulouse, Toulouse, France CNRS; UMR5282, Université de Toulouse, Toulouse, France.
authors.forename: Gabriel
authors.identifier: http://orcid.org/0000-0001-8851-8389
authors.initials: G
authors.lastname: Cuevas-Ramos
authors.affiliation: 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.
authors.forename: Eric
authors.initials: E
authors.lastname: Oswald
authors.affiliation: Clermont Université, Université d'Auvergne; Inserm U1071; INRA USC2018, Clermont-Ferrand, France Institut Universitaire de Technologie, Université d'Auvergne, Aubière, France.
authors.forename: Arlette
authors.initials: A
authors.lastname: Darfeuille-Michaud
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Prati
authors.affiliation: Clermont Université, Université d'Auvergne; Inserm U1071; INRA USC2018, Clermont-Ferrand, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Dalmasso
authors.affiliation: Clermont Université, Université d'Auvergne; Inserm U1071; INRA USC2018, Clermont-Ferrand, France Centre Hospitalier Universitaire, Clermont-Ferrand, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Bonnet
mesh_terms: D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology*; D002135:Calcium-Binding Proteins / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000382:microbiology / Q000517:prevention & control*; D004249:DNA Damage / Q000502:physiology; D004926:Escherichia coli / Q000187:drug effects* / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D009153:Mutagens; D010455:Peptides / Q000378:metabolism*; D061065:Polyketides / Q000378:metabolism*
chemical_list: D001897:Boronic Acids; D002135:Calcium-Binding Proteins; D008024:Ligands; D009153:Mutagens; D010455:Peptides; D061065:Polyketides; C569566:colibactin
keywords: ADJUVANT TREATMENT; BACTERIAL PATHOGENESIS; COLORECTAL CANCER; DRUG DEVELOPMENT; E. COLI