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La estructura cristalográfica de rayos X de un derivado de la teixobactina revela un conjunto de tipo amiloide
Hyunjun Yang1, Michał Wierzbicki1, Derek R Du Bois1
1Department of Chemistry , University of California, Irvine , Irvine , California 92697-2025 , United States.
Journal of the American Chemical Society
|October 9, 2018
Resumen
El derivado del antibiótico teixobactina forma fibrillas parecidas a las amiloides. Estas estructuras crean sitios de unión para los aniones, lo que sugiere un mecanismo para apuntar a los precursores de la pared celular bacteriana.
Área de la Ciencia:
- La bioquímica
- Biología estructural
- Investigación antimicrobiana
Sus antecedentes:
- La teixobactina es un potente antibiótico eficaz contra las bacterias Gram-positivas.
- Comprender el mecanismo de acción de la teixobactina es crucial para combatir la resistencia a los antibióticos.
- Las propiedades de autoensamblaje de los antibióticos pueden influir en su eficacia e interacciones objetivo.
Objetivo del estudio:
- Para aclarar la estructura cristalográfica de rayos X de los derivados de la teixobactina.
- Investigar el ensamblaje supramolecular de la teixobactina y su papel en la unión.
- Proponer un mecanismo de acción para la teixobactina basado en su conjunto estructural.
Principales métodos:
- Se utilizó la cristalografía de rayos X para determinar la estructura de los derivados de teixobactina.
- Se emplearon ensayos de fluorescencia de tioflavina T y microscopía electrónica de transmisión (TEM) para estudiar la formación de fibrillas.
- Se utilizaron técnicas biofísicas para analizar la unión aniónica a las estructuras ensambladas.
Principales resultados:
- Un derivado activo de la teixobactina se autoensambla en fibrillas tipo amiloide.
- Un derivado modificado de la teixobactina cristalizado como doble hélice de hojas β.
- Estos conjuntos de hojas β exhiben sitios de unión para aniones, como el sulfato.
- El metalamonio N-terminal y el macrociclo C-terminal de los dímeros de la hoja β están involucrados en la unión de aniones.
Conclusiones:
- Los derivados de la teixobactina se ensamblan en estructuras de orden superior, formando bolsas de unión de aniones.
- Se propone que este mecanismo de autoensamblaje sea esencial para la capacidad de la teixobactina para unirse al lípido II y a los precursores de la pared celular bacteriana.
- Los resultados proporcionan información sobre la relación estructura-actividad de la teixobactina y su potencial como agente terapéutico.
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