Discovery and Optimization of nTZDpa as an Antibiotic Effective Against Bacterial Persisters.
ACS Infect Dis
; 4(11): 1540-1545, 2018 11 09.
Article
en En
| MEDLINE
| ID: mdl-30132650
ABSTRACT
Conventional antibiotics are not effective in treating infections caused by drug-resistant or persistent nongrowing bacteria, creating a dire need for the development of new antibiotics. We report that the small molecule nTZDpa, previously characterized as a nonthiazolidinedione peroxisome proliferator-activated receptor gamma partial agonist, kills both growing and persistent Staphylococcus aureus cells by lipid bilayer disruption. S. aureus exhibited no detectable development of resistance to nTZDpa, and the compound acted synergistically with aminoglycosides. We improved both the potency and selectivity of nTZDpa against MRSA membranes compared to mammalian membranes by leveraging synthetic chemistry guided by molecular dynamics simulations. These studies provide key insights into the design of selective and potent membrane-active antibiotics effective against bacterial persisters.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Sulfuros
/
Staphylococcus aureus Resistente a Meticilina
/
Descubrimiento de Drogas
/
Indoles
/
Antibacterianos
Límite:
Humans
Idioma:
En
Revista:
ACS Infect Dis
Año:
2018
Tipo del documento:
Article
País de afiliación:
Estados Unidos