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Bases estructurales para la inhibición de las bacterias exportadoras de múltiples fármacos
Ryosuke Nakashima1, Keisuke Sakurai, Seiji Yamasaki
1Department of Cell Membrane Biology, Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka 567-0047, Japan.
Nature
|July 2, 2013
Resumen
Los derivados de piridopirimidina bloquean las bombas de eflujo multidrogas AcrB y MexB al unirse a una trampa hidrofóbica, lo que dificulta su función. Este descubrimiento ayuda en el desarrollo de nuevos antibióticos contra patógenos Gram-negativos.
Área de la Ciencia:
- Biología Estructural Biología estructural.
- Microbiología Microbiología.
- Descubrimiento de Drogas Descubrimiento de Drogas
Sus antecedentes:
- Los transportadores de eflujo de múltiples fármacos como el AcrB son clave para la resistencia a múltiples fármacos en las bacterias Gram-negativas.
- Los inhibidores de la bomba de eflujo existentes carecen de utilidad clínica, lo que requiere nuevas estrategias terapéuticas.
- MexB y MexY son exportadores críticos de múltiples fármacos en Pseudomonas aeruginosa, un patógeno significativo.
Objetivo del estudio:
- Determinar la base estructural de la inhibición de AcrB y MexB por los derivados de piridopirimidina.
- Para dilucidar el mecanismo por el cual las piridopirimidinas impiden la rotación funcional de estas bombas de eflujo.
- Identificar las características estructurales que permiten la unión de inhibidores específicos y guiar el desarrollo de nuevos fármacos.
Principales métodos:
- Determinación de las estructuras cristalinas de AcrB y MexB en complejo con un derivado de piridopirimidina.
- Análisis de los sitios de unión al inhibidor, centrándose en el bolsillo distal y las características hidrofóbicas asociadas.
- Comparación de las interacciones de unión en AcrB, MexB y el transportador relacionado MexY.
Principales resultados:
- Los derivados de piridopirimidina se unen a una trampa hidrofóbica específica en el bolsillo distal de AcrB y MexB.
- Esta unión estéril impide la rotación funcional esencial para el eflujo de fármacos.
- Los residuos de fenilalanina (Phe178) en AcrB y MexB facilitan la unión estrecha del inhibidor a través de interacciones π-π, mientras que el triptófano en MexY (Trp177) lo previene.
Conclusiones:
- La trampa hidrofóbica identificada es un objetivo crítico para los inhibidores basados en piridopirimidina.
- Comprender estas interacciones estructurales es crucial para diseñar inhibidores potentes y específicos de AcrB y MexB.
- Este trabajo sienta las bases para el desarrollo de inhibidores universales dirigidos a MexB y MexY en Pseudomonas aeruginosa.
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