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PA-824 mata a Mycobacterium tuberculosis no replicante mediante la liberación de NO intracelular
Ramandeep Singh1, Ujjini Manjunatha, Helena I M Boshoff
1Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
Science (New York, N.Y.)
|November 29, 2008
Resumen
Los nitroimidazoles cíclicos como el PA-824 son activados por Rv3547 en metabolitos des-nitro. Estos metabolitos generan óxido nítrico (NO), que es crucial para matar a Mycobacterium tuberculosis de forma anaeróbica.
Área de la Ciencia:
- Microbiología Microbiología.
- Descubrimiento de Drogas Descubrimiento de Drogas
- La bioquímica es la bioquímica.
Sus antecedentes:
- Los nitroimidazoles bicíclicos, ejemplificados por el PA-824, son prometedores para el tratamiento de la tuberculosis.
- Estos compuestos funcionan como prodrogas, lo que requiere la activación intracelular para la eficacia.
- La tuberculosis por Mycobacterium (Mtb) plantea un desafío significativo para la salud mundial, que requiere nuevas estrategias terapéuticas.
Objetivo del estudio:
- Para aclarar el mecanismo de activación de los nitroimidazoles bicíclicos, específicamente PA-824.
- Identificar las enzimas y metabolitos clave involucrados en la bioactivación del PA-824.
- Comprender el papel de los metabolitos en la actividad anti-tubercular de estos compuestos.
Principales métodos:
- Pruebas enzimáticas para identificar la nitrorreductaza responsable de la activación del PA-824.
- Identificación y cuantificación de los metabolitos mediante técnicas cromatográficas y espectroscópicas.
- Pruebas in vitro de susceptibilidad de Mtb al PA-824 y sus metabolitos en condiciones anaerobias.
- Evaluación de la generación de especies reactivas de nitrógeno y el efecto de los carroñeros de NO.
Principales resultados:
- Rv3547, una nitrorreductaza (Ddn) dependiente de la deazaflavina, fue identificada como la enzima que activa el PA-824.
- El principal metabolito formado es el des-nitroimidazol (des-nitro).
- Se observó una fuerte correlación entre la formación del metabolito des-nitro y la matanza anaeróbica de Mtb.
- La formación de metabolitos condujo a la generación de especies reactivas de nitrógeno, incluido el óxido nítrico (NO).
- Los carroñeros de óxido nítrico protegieron a Mtb de los efectos letales de la droga.
Conclusiones:
- PA-824 es activado por Rv3547 (Ddn) para des-nitro metabolitos.
- Estos metabolitos funcionan como donantes intracelulares de óxido nítrico (NO), mediando la matanza anaeróbica de Mtb.
- El mecanismo de acción puede implicar aumentar la respuesta inmune innata del huésped a través de la generación de NO.
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