An allosteric inhibitor of Mycobacterium tuberculosis ArgJ: Implications to a novel combinatorial therapy.
EMBO Mol Med
; 10(4)2018 04.
Article
en En
| MEDLINE
| ID: mdl-29483133
ABSTRACT
The existing treatment regime against tuberculosis is not adequate, and novel therapeutic interventions are required to target Mycobacterium tuberculosis (Mtb) pathogenesis. We report Pranlukast (PRK) as a novel allosteric inhibitor of Mtb's arginine biosynthetic enzyme, Ornithine acetyltransferase (MtArgJ). PRK treatment remarkably abates the survival of free as well as macrophage-internalized Mtb, and shows enhanced efficacy in combination with standard-of-care drugs. Notably, PRK also reduces the 5-lipoxygenase (5-LO) signaling in the infected macrophages, thereby surmounting an enhanced response against intracellular pathogen. Further, treatment with PRK alone or with rifampicin leads to significant decrease in Mtb burden and tubercular granulomas in Mtb-infected mice lungs. Taken together, this study demonstrates a novel allosteric inhibitor of MtArgJ, which acts as a dual-edged sword, by targeting the intracellular bacteria as well as the bacterial pro-survival signaling in the host. PRK is highly effective against in vitro and in vivo survival of Mtb and being an FDA-approved drug, it shows a potential for development of advanced combinatorial therapy against tuberculosis.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
2_ODS3
Problema de salud:
2_enfermedades_transmissibles
Asunto principal:
Tuberculosis
/
Mycobacterium tuberculosis
/
Antituberculosos
Límite:
Animals
Idioma:
En
Revista:
EMBO Mol Med
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2018
Tipo del documento:
Article
País de afiliación:
India