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Inhibidores de moléculas pequeñas de la interacción BfrB-Bfd Disminuir la aptitud de Pseudomonas aeruginosa y
Achala N D Punchi Hewage1, Huili Yao2, Baskar Nammalwar3
1Department of Chemistry , University of Kansas , 2030 Becker Drive , Lawrence , Kansas 66047 , United States.
Journal of the American Chemical Society
|May 1, 2019
Resumen
Los investigadores desarrollaron inhibidores de moléculas pequeñas dirigidos a la proteína bacteriana de almacenamiento de hierro bacterioferritina (BfrB) y su interacción con la ferredoxina (Bfd). Estos inhibidores alteran la homeostasis del hierro en P. aeruginosa, mostrando potencial en las terapias combinadas.
Área de la Ciencia:
- La homeostasis bacteriana del hierro
- Inhibidores de la interacción proteína-proteína
- Descubrimiento de drogas
Sus antecedentes:
- La bacterioferritina (BfrB) es crucial para el almacenamiento de hierro bacteriano y la homeostasis.
- La movilización de hierro de BfrB por ferredoxina (Bfd) regula los niveles de hierro citosólico en P. aeruginosa.
- Dirigirse a las interacciones proteína-proteína ofrece una nueva estrategia terapéutica.
Objetivo del estudio:
- Para desarrollar inhibidores de molécula pequeña de la interacción proteína-proteína BfrB-Bfd.
- Investigar el impacto de estos inhibidores en la homeostasis y el crecimiento del hierro de P. aeruginosa.
- Evaluar el potencial de estos inhibidores en combinación con antibióticos.
Principales métodos:
- Diseño de fármacos guiado por la estructura basado en la selección de fragmentos.
- Síntesis y caracterización de los análogos de la isoindolina-1,3-diona sustituida por 4.
- Ensayos in vitro e in vivo con P. aeruginosa, incluida la inhibición del crecimiento y la tinción del hierro.
Principales resultados:
- Desarrolló análogos de isoindolina que se unen selectivamente a BfrB en el sitio de unión de Bfd.
- Los inhibidores provocaron una inhibición del crecimiento dependiente de la dosis y una hiperproducción de pioverdina en P. aeruginosa.
- Los análogos condujeron a la acumulación de hierro en BfrB y al agotamiento en el citosol, confirmado por la tinción nativa de PAGE y Fereno S.
- El tratamiento combinado con fluoroquinolonas redujo significativamente la supervivencia de P. aeruginosa.
Conclusiones:
- Los inhibidores de moléculas pequeñas dirigidos a la interacción BfrB-Bfd desregulan efectivamente la homeostasis bacteriana del hierro.
- Estos hallazgos demuestran una prueba de concepto para apuntar a las interacciones proteína-proteína en el almacenamiento de hierro bacteriano.
- Los análogos desarrollados son prometedores como complementos de las terapias antibióticas existentes.
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