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Nueva Delhi metallo-β-lactamasa: conocimientos estructurales sobre el reconocimiento y la inhibición del β-lactamo
Dustin T King1, Liam J Worrall, Robert Gruninger
1Department of Biochemistry and Molecular Biology and Center for Blood Research, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3.
Journal of the American Chemical Society
|June 21, 2012
Resumen
La enzima metalo-β-lactamasa-1 (NDM-1) de Nueva Delhi confiere resistencia a los antibióticos β-lactámicos críticos. El análisis estructural revela cómo el NDM-1 interactúa con los carbapenems y los inhibidores, guiando el desarrollo de nuevos medicamentos.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Estructural Biología estructural.
- La resistencia a los antimicrobianos se ha desarrollado.
Sus antecedentes:
- La metalo-β-lactamasa-1 de Nueva Delhi (NDM-1) es un factor significativo de resistencia a los antibióticos.
- NDM-1 confiere resistencia a casi todos los antibióticos β-lactámicos, incluidos los carbapenems, lo que representa una amenaza para la salud mundial.
Objetivo del estudio:
- Para dilucidar los mecanismos moleculares de la resistencia a los antibióticos mediada por NDM-1.
- Para determinar las estructuras cristalinas de alta resolución de NDM-1 en complejo con varios sustratos e inhibidores.
- Proporcionar ideas para el diseño racional de nuevos inhibidores de NDM-1.
Principales métodos:
- Se utilizó cristalografía de rayos X para determinar las estructuras de NDM-1.
- Se resolvieron estructuras complejas para el NDM-1 unido al meropenem, la bencilpenicilina hidrolizada, la meticilina, la oxacilina y el l-captopril.
- Se obtuvieron datos de alta resolución (hasta 1,2 Å) para complejos de productos.
Principales resultados:
- La estructura cristalina de NDM-1 unido al meropenem revela el mecanismo de reconocimiento de los antibióticos carbapenémicos.
- Las estructuras de mayor resolución de cualquier metallo-β-lactamasa hasta la fecha se lograron para los complejos de productos NDM-1.
- La estructura de NDM-1 unido a l-captopril muestra un mecanismo de unión único para un inhibidor competitivo.
Conclusiones:
- Los conocimientos estructurales sobre la interacción del NDM-1-meropenem son cruciales para comprender la resistencia al carbapenem.
- Los datos estructurales de alta resolución facilitan el análisis detallado del sitio activo NDM-1.
- Comprender las características del sitio activo de NDM-1 es clave para diseñar inhibidores efectivos contra las metallo-β-lactamasas.
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