Article Text

PDF
Original article
Small-molecule inhibitors prevent the genotoxic and protumoural effects induced by colibactin-producing bacteria
  1. Antony Cougnoux1,
  2. Julien Delmas1,2,
  3. Lucie Gibold1,2,
  4. Tiphanie Faïs1,
  5. Chiara Romagnoli3,
  6. Frederic Robin1,2,
  7. Gabriel Cuevas-Ramos4,5,6,
  8. Eric Oswald4,5,6,7,8,
  9. Arlette Darfeuille-Michaud1,9,,
  10. Fabio Prati3,
  11. Guillaume Dalmasso1,
  12. Richard Bonnet1,2
  1. 1Clermont Université, Université d'Auvergne; Inserm U1071; INRA USC2018, Clermont-Ferrand, France
  2. 2Centre Hospitalier Universitaire, Clermont-Ferrand, France
  3. 3Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
  4. 4INRA; USC 1360, Université de Toulouse, Toulouse, France
  5. 5Inserm; UMR1043, Université de Toulouse, Toulouse, France
  6. 6CNRS; UMR5282, Université de Toulouse, Toulouse, France
  7. 7UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France
  8. 8CHU Toulouse; Hôpital Purpan; Service de bactériologie-Hygiène, Toulouse, France
  9. 9Institut Universitaire de Technologie, Université d'Auvergne, Aubière, France
  1. Correspondence to Dr Richard Bonnet, CHU, Laboratoire de Bacteriologie, 58 rue Montalembert, Clermont-Ferrand 63000, France; rbonnet{at}chu-clermontferrand.fr

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.

  • COLORECTAL CANCER
  • ADJUVANT TREATMENT
  • BACTERIAL PATHOGENESIS
  • DRUG DEVELOPMENT
  • E. COLI

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.