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Activación para la catálisis de la proteína 2a de unión a la penicilina de Staphylococcus aureus resistente a la
Cosimo Fuda1, Dusan Hesek, Mijoon Lee
1Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, USA.
Journal of the American Chemical Society
|February 17, 2005
Resumen
El Staphylococcus aureus resistente a la meticilina (MRSA, por sus siglas en inglés) utiliza una proteína única, PBP 2a, para resistir los antibióticos. Los fragmentos de la pared celular bacteriana se unen a la PBP 2a, revelando su sitio activo a los antibióticos solo durante la reparación esencial de la pared celular.
Área de la Ciencia:
- Microbiología Microbiología.
- Biología Estructural Biología estructural.
- Descubrimiento de Drogas Descubrimiento de Drogas
Sus antecedentes:
- El Staphylococcus aureus resistente a la meticilina (MRSA por sus siglas en inglés) representa una amenaza significativa para la salud pública.
- La resistencia de MRSA a los antibióticos beta-lactámicos está mediada por la proteína única que se une a la penicilina, PBP 2a.
- El sitio activo de la PBP 2a exhibe una conformación cerrada, lo que dificulta la unión a los antibióticos.
Objetivo del estudio:
- Para investigar el mecanismo de la función y la resistencia de PBP 2a.
- Para entender cómo PBP 2a interactúa con su sustrato fisiológico.
- Identificar las posibles vulnerabilidades en el mecanismo de resistencia del SARM.
Principales métodos:
- Cristalografía de rayos X para determinar la estructura de PBP 2a.
- Ensayos de unión utilizando fragmentos sintéticos de paredes celulares de bacterias.
- Análisis de conformación de PBP 2a después de la unión al sustrato.
Principales resultados:
- El sitio activo de PBP 2a es conformacionalmente flexible.
- Los fragmentos de la pared celular bacteriana se unen de forma saturable a la PBP 2a.
- La unión de fragmentos de la pared celular induce un cambio conformacional, abriendo el sitio activo de PBP 2a.
Conclusiones:
- El SARM emplea un nuevo mecanismo para proteger a la PBP 2a de los antibióticos.
- El sitio activo de PBP 2a se protege hasta que la síntesis de la pared celular requiera su función.
- Esta regulación conformacional presenta un objetivo potencial para el desarrollo de nuevos antibióticos contra MRSA.
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