Screening of a Drug Library Identifies Inhibitors of Cell Intoxication by CNF1.
ChemMedChem
; 13(7): 754-761, 2018 04 06.
Article
em En
| MEDLINE
| ID: mdl-29359495
ABSTRACT
Cytotoxic necrotizing factorâ
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
3_ND
Base de dados:
MEDLINE
Assunto principal:
Toxinas Bacterianas
/
Proteínas rac1 de Ligação ao GTP
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Proteínas de Escherichia coli
/
Bibliotecas de Moléculas Pequenas
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Limite:
Humans
Idioma:
En
Revista:
ChemMedChem
Ano de publicação:
2018
Tipo de documento:
Article