3 years ago

Screening of drug library identifies inhibitors of cell intoxication by CNF1

Orane Visvikis, Daniel Gillet, Emmanuel Lemichez, Nassim Mahtal, Sylvain Pichard, Julien Barbier, Jean-Christophe Cintrat, Clémence Brewee
The 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 1,120 mostly approved drugs. Eleven compounds prevented CNF1-induced Rac1 degradation and five showed also a protective effect on CNF1-induced multinucleation. At last, lasalocid, monensin, bepridil and amodiaquine protect cells from both diphtheria toxin and CNF1 challenges. These data highlight potential drug repositioning to fight several bacterial toxi-infections and Rac1-based diseases.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/cmdc.201700631

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