Small-molecule targeting of a diapophytoene desaturase inhibits S. aureus virulence.
Nat Chem Biol
; 12(3): 174-9, 2016 Mar.
Article
em En
| MEDLINE
| ID: mdl-26780405
ABSTRACT
The surge of antibiotic resistance in Staphylococcus aureus has created a dire need for innovative anti-infective agents that attack new targets, to overcome resistance. In S. aureus, carotenoid pigment is an important virulence factor because it shields the bacterium from host oxidant killing. Here we show that naftifine, a US Food and Drug Administration (FDA)-approved antifungal drug, blocks biosynthesis of carotenoid pigment at nanomolar concentrations. This effect is mediated by competitive inhibition of S. aureus diapophytoene desaturase (CrtN), an essential enzyme for carotenoid pigment synthesis. We found that naftifine attenuated the virulence of a variety of clinical S. aureus isolates, including methicillin-resistant S. aureus (MRSA) strains, in mouse infection models. Specifically, we determined that naftifine is a lead compound for potent CrtN inhibitors. In sum, these findings reveal that naftifine could serve as a chemical probe to manipulate CrtN activity, providing proof of concept that CrtN is a druggable target against S. aureus infections.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Oxirredutases
/
Staphylococcus aureus
/
Proteínas de Bactérias
/
Alilamina
/
Antibacterianos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Nat Chem Biol
Assunto da revista:
BIOLOGIA
/
QUIMICA
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
China