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Conocimientos estructurales sobre la inhibición de la producción de lípidos I en la síntesis de la pared celular

Ben C Chung¹, Ellene H Mashalidis¹, Tetsuya Tanino²

¹Department of Biochemistry, Duke University Medical Center, 303 Research Drive, Durham, North Carolina, 27710, USA.

|April 19, 2016

Resumen

Los conocimientos estructurales sobre la inhibición de MraY por la muramicina D2 revelan grandes cambios conformacionales. La comprensión de estos mecanismos puede guiar el desarrollo de nuevos antibióticos dirigidos a la biosíntesis de peptidoglicanos bacterianos.

Área de la Ciencia:

Microbiología
Biología estructural
Descubrimiento de drogas

Sus antecedentes:

Las infecciones bacterianas resistentes a los antibióticos representan una amenaza significativa para la salud mundial.
La biosíntesis de peptidoglicanos es un objetivo validado para el desarrollo de nuevos antibióticos.
MraY (translocación de fosfo-MurNAc-pentapéptido) es una enzima crucial en la síntesis de peptidoglicanos y un objetivo antibiótico prometedor.

Objetivo del estudio:

Para aclarar la base estructural de la inhibición de MraY por su inhibidor natural de nucleósidos, la muramicina D2.
Comprender los cambios conformacionales en MraY tras la unión al inhibidor.
Proporcionar ideas para el diseño de nuevos antibióticos dirigidos a MraY.

Principales métodos:

Se utilizó la cristalografía de rayos X para determinar la estructura de Aquifex aeolicus MraY (MraYAA) en complejo con muraymicina D2 (MD2).
Análisis de la estructura cristalina para identificar las interacciones de unión y los cambios conformacionales.

Principales resultados:

La estructura cristalina revela grandes reordenamientos conformacionales en MraYAA sobre la unión MD2, creando sitios de unión de nucleósidos y péptidos distintos.
MD2 se une a través de un mecanismo único, anclando a MraYAA sin interactuar con los residuos catalíticos clave o el cofactor Mg2+.
La unión MD2 difiere del sustrato natural, UDP-MurNAc-pentapeptídeo, al no requerir fracciones de pirofosfato y azúcar para la interacción.

Conclusiones:

La plasticidad conformacional de MraY facilita la unión de diversos inhibidores.
Los principios de unión determinados de MD2 a MraYAA ofrecen una base para el diseño de nuevos antibióticos contra MraY y enzimas relacionadas como WecA y TarO.
Esta información estructural es fundamental para avanzar en el desarrollo de agentes antibacterianos que se necesitan con urgencia.

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