Screening of a Drug Library Identifies Inhibitors of Cell Intoxication by CNF1

Nassim Mahtal (1, 2) , Clémence Brewee (1) , Sylvain Pichard (1) , Orane Visvikis (3) , Jean-Christophe Cintrat (2) , Julien Barbier (1) , Emmanuel Lemichez (3) , Daniel Gillet (1)

1 SIMoS - Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO)
2 SCBM - Service de Chimie Bio-Organique et de Marquage
3 C3M - Centre méditerranéen de médecine moléculaire

Cytotoxic necrotizing factor 1 (CNF1) is a toxin produced by pathogenic strains of Escherichia coli responsible for extra‐intestinal infections. CNF1 deamidates Rac1, thereby triggering its permanent activation and worsening inflammatory reactions. Activated Rac1 is prone to proteasomal degradation. There is no targeted therapy against CNF1, despite its clinical relevance. In this work we developed a fluorescent cell‐based immunoassay to screen for inhibitors of CNF1‐induced Rac1 degradation among 1120 mostly approved drugs. Eleven compounds were found to prevent CNF1‐induced Rac1 degradation, and five also showed a protective effect against CNF1‐induced multinucleation. Finally, lasalocid, monensin, bepridil, and amodiaquine protected cells from both diphtheria toxin and CNF1 challenges. These data highlight the potential for drug repurposing to fight several bacterial infections and Rac1‐based diseases.

Mots clés: CNF1; Rac1; drug discovery; inhibitors; screening

Domaines: Sciences du Vivant [q-bio]; Microbiologie et Parasitologie; Bactériologie; Biologie cellulaire; Organisation et fonctions cellulaires [q-bio.SC]; Interactions cellulaires [q-bio.CB]

Nassim Mahtal, Clémence Brewee, Sylvain Pichard, Orane Visvikis, Jean-Christophe Cintrat, et al.. Screening of a Drug Library Identifies Inhibitors of Cell Intoxication by CNF1. ChemMedChem, 2018, 13 (7), pp.754-761. ⟨10.1002/cmdc.201700631⟩. ⟨pasteur-02448858⟩