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Adaptación de un sistema bacteriano de resistencia a múltiples fármacos revelada por la estructura y la función de

Asfandyar Sikandar¹, Katarina Cirnski^2,3, Giambattista Testolin^3,4

¹Workgroup Structural Biology of Biosynthetic Enzymes, Helmholtz Institute for Pharmaceutical Research Saarland , Helmholtz Centre for Infection Research, Saarland University , Campus Geb. E8.1 , Saarbrücken 66123 , Germany.

Journal of the American Chemical Society

|November 14, 2018

Resumen

Una nueva investigación revela cómo la proteína neutralizadora de antibióticos AlbA se une y modifica el antibiótico albicidina. Esta proteína evolucionó a partir de un antiguo gen, ofreciendo información sobre los mecanismos de resistencia a los antibióticos y las posibles estrategias de descubrimiento de nuevos medicamentos.

Área de la Ciencia:

Microbiología
Biología estructural
Descubrimiento de drogas

Sus antecedentes:

La resistencia a los antimicrobianos hace necesario el descubrimiento de nuevos antibióticos.
La albicidina y la cistobactamida son potentes antibióticos eficaces contra los patógenos Gram-positivos y Gram-negativos.
La proteína A neutralizadora de la albicidina (AlbA) es un mecanismo de resistencia potencial.

Objetivo del estudio:

Para aclarar la base estructural de la interacción de AlbA con la albicidina.
Para entender el mecanismo por el cual AlbA neutraliza la albicidina.
Para investigar el origen evolutivo de AlbA.

Principales métodos:

Cristalografía de rayos X para determinar las estructuras de AlbA y su complejo con albicidina.
Ensayos bioquímicos para demostrar la modificación de la albicidina.
El análisis bioinformático para inferir las relaciones evolutivas.

Principales resultados:

La estructura de AlbA reveló dos dominios, cada uno similar a la proteína neutralizadora multiantibiótica TipA.
La unión a la albicidina se distribuyó pseudo simétricamente en ambos dominios de AlbA.
AlbA promueve una inesperada modificación química de la albicidina, reduciendo su potencia.

Conclusiones:

AlbA probablemente evolucionó de un antiguo gen tipo TipA a través de la duplicación interna.
Los hallazgos proporcionan una comprensión estructural de la neutralización y la resistencia a la albicidina.
Este trabajo ofrece información sobre la evolución de las proteínas de unión a los antibióticos y las posibles vías para el desarrollo de nuevos antibióticos.

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