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Inhibición de la M. tuberculosis y de la ATP sintasa humana por BDQ y TBAJ-587

Yuying Zhang¹, Yuezheng Lai¹, Shan Zhou¹

¹State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin, China.

|July 3, 2024

Resumen

Bedaquilina y TBAJ-587 inhiben el crecimiento de la tuberculosis al dirigirse a la ATP sintasa. Las estructuras cryo-EM revelan sitios de unión similares en M. tuberculosis y ATP sintasa humana, ayudando al diseño de nuevos fármacos.

Área de la Ciencia:

La bioquímica
Biología estructural
Descubrimiento de drogas

Sus antecedentes:

Bedaquilina (BDQ) es un fármaco antituberculoso crucial dirigido a la ATP sintasa de Mycobacterium tuberculosis.
BDQ también inhibe la ATP sintasa humana, lo que plantea preocupaciones de seguridad.
Los mecanismos precisos de interacción de BDQ y sus análogos con las ATP sintasas siguen siendo incompletamente conocidos.

Objetivo del estudio:

Para aclarar la base estructural de la Bedaquilina (BDQ) y el TBAJ-587 que se unen a la ATP sintasa de Mycobacterium tuberculosis.
Para determinar la estructura de la ATP sintasa humana en complejo con BDQ.
Comparar los modos de unión de BDQ en M. tuberculosis y las ATP sintasas humanas para el diseño racional de fármacos.

Principales métodos:

Se empleó microscopía electrónica criogénica (cryo-EM) para determinar las estructuras de alta resolución.
Se obtuvieron estructuras para la ATP sintasa de M. tuberculosis con y sin BDQ y TBAJ-587.
También se determinó la estructura de la ATP sintasa humana compleja con BDQ.

Principales resultados:

Las estructuras cryo-EM revelan que BDQ y TBAJ-587 se unen a la ATP sintasa de M. tuberculosis en múltiples sitios, incluida la subunidad a y el anillo c.
Ambos compuestos presentan modos de acción similares contra la ATP sintasa de M. tuberculosis.
El sitio de unión de BDQ en la ATP sintasa humana es estructuralmente similar a un sitio clave en la ATP sintasa de M. tuberculosis, con amplias interacciones observadas.

Conclusiones:

BDQ y TBAJ-587 comparten interacciones de unión similares dentro de la ATP sintasa de M. tuberculosis.
La similitud estructural en la unión de BDQ entre M. tuberculosis y las ATP sintasas humanas proporciona información sobre posibles efectos fuera del objetivo.
Estos hallazgos facilitan el diseño racional de nuevos derivados de diarilquinolina con mejores perfiles de eficacia y seguridad contra la tuberculosis.

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