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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Una vía similar al receptor nuclear que regula la resistencia a múltiples fármacos en los hongos
Jitendra K Thakur1, Haribabu Arthanari, Fajun Yang
1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USA.
Nature
|April 4, 2008
Resumen
Los investigadores descubrieron cómo los factores de transcripción fúngicos regulan la resistencia a múltiples fármacos (MDR). Este estudio revela un mecanismo conservado para la resistencia a los medicamentos en hongos y vertebrados, ofreciendo nuevos objetivos terapéuticos para infecciones fúngicas difíciles de tratar.
Área de la Ciencia:
- La micología médica La micología médica.
- Biología Molecular Biología Molecular
- Descubrimiento de Drogas Descubrimiento de Drogas
Sus antecedentes:
- La resistencia a múltiples fármacos (MDR) complica el tratamiento de las infecciones fúngicas oportunistas en pacientes inmunocomprometidos.
- La upregulación de las bombas de eflujo de fármacos por los factores de transcripción fúngicos de clúster de zinc es un mecanismo clave de la MDR, pero poco comprendido.
Objetivo del estudio:
- Para dilucidar los mecanismos moleculares subyacentes MDR en hongos patógenos.
- Identificar nuevos objetivos terapéuticos para combatir las infecciones fúngicas resistentes a los medicamentos.
Principales métodos:
- Los miembros de la familia Pdr1p investigados en Saccharomyces cerevisiae y Candida glabrata.
- Se analizó el papel de la subunidad Gal11p/MED15 del coactivador Mediador y su dominio KIX.
Principales resultados:
- Los miembros de la familia Pdr1p se unen directamente a los fármacos, induciendo la expresión de la bomba de eflujo y la MDR.
- Se encontró una analogía funcional entre los reguladores fúngicos y los receptores nucleares PXR de los vertebrados.
- La subunidad Gal11p/MED15 y su dominio KIX juegan un papel crítico en la regulación de la MDR.
Conclusiones:
- Comprensión mecanicista detallada de las vías reguladoras de genes similares a los receptores nucleares de hongos.
- Se han identificado nuevos objetivos terapéuticos para el tratamiento de infecciones fúngicas multirresistentes.
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