Hybrid Antibiotic Overcomes Resistance in P. aeruginosa by Enhancing Outer Membrane Penetration and Reducing Efflux.
J Med Chem
; 59(18): 8441-55, 2016 09 22.
Article
en En
| MEDLINE
| ID: mdl-27524179
ABSTRACT
Therapeutic interventions to treat multidrug-resistant (MDR) Pseudomonas aeruginosa infections are severely limited and often require the use of colistin as drug of last resort. The major challenges impeding the development of novel antipseudomonal agents are the lack of cell penetration and extensive efflux. We have discovered a tobramycin-moxifloxacin hybrid core structure which enhances outer membrane permeability and reduces efflux by dissipating the proton motive force of the cytoplasmic membrane in P. aeruginosa. The optimized hybrid protects Galleria mellonella larvae from the lethal effects of MDR P. aeruginosa. Attempts to select for resistance over a period of 25 days resulted in a 2-fold increase in the minimal inhibitory concentration (MIC) for the hybrid, while moxifloxacin or tobramycin resulted in a 16- and 512-fold increase in MIC. Although the hybrid possesses potent activity against MDR, P. aeruginosa isolates the activity that can be synergized when used in combination with other classes of antibiotics.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Pseudomonas aeruginosa
/
Tobramicina
/
Fluoroquinolonas
/
Antibacterianos
Límite:
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2016
Tipo del documento:
Article
País de afiliación:
Canadá