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© Emmanuel Lemichez
Microscopy image showing the formation of large tunnels in a blood vessel endothelial cell induced by a group of bacterial toxins
Publication : ChemMedChem

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

Team: Bacterial Toxins
Team: Photonic BioImaging (UTechS PBI)
Member: Emmanuel Lemichez
Member: Nassim Mahtal
Scientific Fields
Diseases
Organisms
Applications
Technique

Published in ChemMedChem - 23 Jan 2018

Mahtal N, Brewee C, Pichard S, Visvikis O, Cintrat JC, Barbier J, Lemichez E, Gillet D,

Link to Pubmed [PMID] – 29359495

Link to DOI – 10.1002/cmdc.201700631

ChemMedChem 2018 04; 13(7): 754-761

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.