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Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection
Published on: October 25, 2013
El reconocimiento de antibióticos por metallo-beta-lactamasas binucleares revelado por la cristalografía de rayos X
James Spencer1, Jonathan Read, Richard B Sessions
1Departments of Cellular and Molecular Medicine and Biochemistry, University of Bristol School of Medical Sciences, University Walk, Bristol BS8 1TD, United Kingdom.
Journal of the American Chemical Society
|October 13, 2005
Resumen
Las metalo-beta-lactamasas (MBL) resisten los antibióticos mediante su hidrólisis. Comprender la estructura de Stenotrophomonas maltophilia L1 MBL revela cómo los iones de zinc y el agua facilitan este proceso, ayudando al desarrollo de inhibidores.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Estructural Biología estructural.
- Microbiología Microbiología.
Sus antecedentes:
- Las metalo-beta-lactamasas (MBL) son cruciales para la resistencia bacteriana a los antibióticos beta-lactámicos.
- Estas enzimas dependientes del zinc hidrolizan diversas clases de antibióticos, incluidos los carbapenems, evitando los inhibidores actuales.
- La falta de datos estructurales dificulta el desarrollo de inhibidores eficaces de la LMB.
Objetivo del estudio:
- Para aclarar las bases estructurales del reconocimiento de sustratos e hidrólisis por metallo-beta-lactamasas.
- Determinar el mecanismo de acción de la enzima Stenotrophomonas maltophilia L1.
Principales métodos:
- Se utilizó la cristalografía de rayos X para determinar la estructura de la enzima L1.
- La enzima fue cristalizada en complejo con moxalactam, un producto de hidrólisis.
Principales resultados:
- La estructura cristalina reveló moxalactam unido a la enzima L1 a través de interacciones con los iones de zinc del sitio activo.
- Las interacciones clave involucran a los grupos beta-lactámicos amida y C4 carboxilato, comunes a todos los sustratos beta-lactámicos.
- Una molécula de agua entre los iones de zinc se identifica como el probable nucleófilo, activado por los iones metálicos.
Conclusiones:
- El sitio de zinc binuclear en MBLs es esencial tanto para el reconocimiento del sustrato como para la hidrólisis eficiente.
- El mecanismo propuesto implica que los iones de zinc activen un nucleófilo de agua y polaricen el sustrato.
- Esta visión estructural proporciona una base para el diseño de nuevos inhibidores de la metallo-beta-lactamasa.
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