Targeting Two-Component Systems Uncovers a Small-Molecule Inhibitor of Salmonella Virulence.
Cell Chem Biol
; 27(7): 793-805.e7, 2020 07 16.
Article
en En
| MEDLINE
| ID: mdl-32413287
ABSTRACT
Salmonella serovars are leading causes of gastrointestinal disease and have become increasingly resistant to fluoroquinolone and cephalosporin antibiotics. Overcoming this healthcare crisis requires new approaches in antibiotic discovery and the identification of unique bacterial targets. In this work, we describe a chemical genomics approach to identify inhibitors of Salmonella virulence. From a cell-based, promoter reporter screen of â¼50,000 small molecules, we identified dephostatin as a non-antibiotic compound that inhibits intracellular virulence factors and polymyxin resistance genes. Dephostatin disrupts signaling through both the SsrA-SsrB and PmrB-PmrA two-component regulatory systems and restores sensitivity to the last-resort antibiotic, colistin. Cell-based experiments and mouse models of infection demonstrate that dephostatin attenuates Salmonella virulence in vitro and in vivo, suggesting that perturbing regulatory networks is a promising strategy for the development of anti-infectives.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Salmonella
/
Virulencia
/
Bibliotecas de Moléculas Pequeñas
/
Antibacterianos
Límite:
Animals
Idioma:
En
Revista:
Cell Chem Biol
Año:
2020
Tipo del documento:
Article
País de afiliación:
Canadá