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Avenaciolides: potenciales inhibidores dirigidos a MurA contra la biosíntesis de peptidoglicanos en el Staphylococcus
Ching-Ming Chang1, Jeffy Chern, Ming-Yi Chen
1Institute of Biological Chemistry, §Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, #Genomics Research Center, and ▽Agricultural Biotechnology Research Center, Academia Sinica , Taipei 115, Taiwan.
Journal of the American Chemical Society
|December 19, 2014
Resumen
Los nuevos avenaciolides de hongos muestran una potente actividad contra el Staphylococcus aureus resistente a la meticilina (MRSA). Estos compuestos se dirigen a MurA, ofreciendo un nuevo enfoque contra las bacterias resistentes a los antibióticos, incluidas las cepas resistentes a la fosfomicina.
Área de la Ciencia:
- Microbiología Microbiología.
- Química Medicinal Química medicinal es el campo de la química medicinal.
- La bioquímica es la bioquímica.
Sus antecedentes:
- El aumento de la resistencia a los antibióticos, en particular el Staphylococcus aureus resistente a la meticilina (MRSA), hace necesario el descubrimiento de nuevos agentes antimicrobianos.
- Los antibióticos existentes se enfrentan a limitaciones, lo que impulsa la investigación de nuevos objetivos terapéuticos y andamios químicos.
Objetivo del estudio:
- Identificar y caracterizar nuevos compuestos con actividad antimicrobiana contra el SARM.
- Para dilucidar el mecanismo de acción y el objetivo farmacológico de estos compuestos.
- Para explorar su potencial contra las cepas bacterianas resistentes a los antibióticos.
Principales métodos:
- Aislamiento y aclaración estructural de los derivados de avenaciolide de Neosartorya fischeri.
- Pruebas de susceptibilidad antimicrobiana contra MRSA.
- (31) Espectroscopia de RMN y análisis de EM/EM para identificar el objetivo del fármaco.
- Simulaciones moleculares para comprender la interacción con la enzima diana.
Principales resultados:
- Tres de los cuatro derivados aislados de avenaciolide (1-4) exhibieron actividad antimicrobiana significativa contra el MRSA.
- Se descubrió que los avenaciolidos interrumpen la biosíntesis de la pared celular bacteriana.
- MurA fue identificado como el objetivo del fármaco, con los avenaciolidos 1 y 2 mostrando actividad tanto contra el MurA de tipo salvaje como contra el resistente a la fosfomicina.
- Se demostró que el Compuesto 2 inhibe competitivamente la actividad de MurA a través de la simulación molecular.
Conclusiones:
- Los avenaciolides representan una nueva clase prometedora de antibióticos dirigidos a MurA.
- Estos compuestos son efectivos contra el SARM y ofrecen un nuevo mecanismo contra las cepas resistentes a la fosfomicina.
- Los hallazgos proporcionan una base para el desarrollo de nuevos antibióticos dirigidos a MurA para combatir las infecciones bacterianas resistentes.
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