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Screening of a Drug Library Identifies Inhibitors of Cell Intoxication by CNF1
Author(s) -
Mahtal Nassim,
Brewee Clémence,
Pichard Sylvain,
Visvikis Orane,
Cintrat JeanChristophe,
Barbier Julien,
Lemichez Emmanuel,
Gillet Daniel
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700631
Subject(s) - rac1 , drug , prodrug , microbiology and biotechnology , diphtheria toxin , pharmacology , drug repositioning , biology , toxin , chemistry , biochemistry , signal transduction
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.