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Monday, 04 April 2022 13:36

Un estudio evolutivo abre la puerta a una estrategia eficaz frente a bacterias resistentes a los antibióticos

Ensayo de sensibilidad a antibióticos en diferentes mutantes de Pseudomonas aeruginosa resistentes a diferentes antibióticos crecidos en placas de cultivo individualmente. En cada placa se observa un halo de inhibición del crecimiento bacteriano causado por el antibiótico presente en cada tira (E-Test). Ensayo de sensibilidad a antibióticos en diferentes mutantes de Pseudomonas aeruginosa resistentes a diferentes antibióticos crecidos en placas de cultivo individualmente. En cada placa se observa un halo de inhibición del crecimiento bacteriano causado por el antibiótico presente en cada tira (E-Test). Sara Hernando-Amado.
  • La adquisición de mutaciones de resistencia a antibióticos puede dar lugar a la sensibilización frente a otros antibióticos, un fenómeno conocido como sensibilidad colateral
  • Comprender la evolución de la resistencia a los antibióticos podría facilitar el diseño de nuevas estrategias terapéuticas utilizando antibióticos de uso habitual

La resistencia de las bacterias a los antibióticos es, tal como indican la OMS y la ONU, uno de los mayores problemas actuales de salud pública. Dicha resistencia hace más difícil -en ocasiones imposible- tratar las infecciones bacterianas, así como desarrollar prácticas clínicas como trasplantes o tratamientos anticancerígenos que requieren un control de posibles infecciones. Entre estas, tienen gran relevancia las causadas por Pseudomonas aeruginosa, uno de los patógenos oportunistas que con mayor frecuencia produce infecciones en pacientes hospitalizados o con patologías previas, incluyendo inmunodeficiencias y fibrosis quística. Esta bacteria tiene una baja sensibilidad a los antibióticos, y una gran capacidad para adquirir mutaciones de resistencia a los mismos, de ahí el interés en encontrar terapias eficaces contra ella. En este contexto, además de desarrollar nuevos antibióticos, algo económicamente costoso, es necesario hacer un mejor uso de los que ya tenemos.

Un nuevo estudio de los investigadores del CSIC Sara Hernando-Amado, Pablo Laborda, José Ramón Valverde y José Luis Martínez publicado en la revista Proceedings of the National Academy of Sciences (PNAS), da un paso más en la búsqueda de alternativas terapéuticas basadas en el uso de antibióticos ya existentes. Analizando la evolución de diferentes mutantes de P. aeruginosa en presencia de distintos antibióticos, han identificado un patrón conservado de sensibilidad frente a otros antibióticos (un fenómeno llamado sensibilidad colateral) que podría tener aplicación clínica.

El equipo del Centro Nacional de Biotecnología (CNB-CSIC) ha realizado un novedoso abordaje experimental basado en ensayos clásicos de evolución experimental bacteriana. Sara Hernando-Amado, investigadora que ha liderado el proyecto, explica “si bien la mayor parte de los estudios sobre sensibilidad colateral han utilizado cepas modelo de laboratorio (relativamente sensibles a los antibióticos), nosotros planteamos que un requisito imprescindible para la aplicación clínica de la sensibilidad colateral es que se produzca en diferentes mutantes previamente resistentes a otros antibióticos, una situación más próxima a la que encontramos en clínica”. “Por ello, en nuestros ensayos de evolución en presencia de antibióticos, hemos utilizando distintos mutantes de P. aeruginosa previamente resistentes a diferentes antibióticos, buscando patrones evolutivos conservados en todos ellos”. “De esta manera, hemos encontrado que la adquisición de mutaciones de resistencia frente al antibiótico ciprofloxacino da lugar a sensibilidad colateral frente a otros dos antibióticos, tobramicina y aztreonam.” La aparición de este patrón de sensibilidad colateral conservado no es frecuente ni fácil desde el punto de vista genético. En base a esto, los investigadores han determinado que el uso combinado de ciprofloxacino-aztreonam o ciprofloxacino-tobramicina produce la eliminación de los mutantes resistentes de P. aeruginosa analizados.

Hernando-Amado indica que “desde un punto de vista evolutivo, se trata de un caso de convergencia fenotípica (en todos los casos se adquiere la misma sensibilidad colateral) causada por la adquisición de diferentes mutaciones de resistencia frente al antibiótico inicialmente administrado”. Esto implica que “si bien las trayectorias evolutivas que puede seguir este patógeno en presencia de ciprofloxacino son diversas, todas ellas derivan en un aumento de sensibilidad a tobramicina y aztreonam, lo que sugiere una posible aplicación clínica”.

Los ensayos de evolución experimental como los realizados en esta investigación permiten entender la evolución de la resistencia y la sensibilidad colateral a los antibióticos. Este trabajo demuestra que es posible identificar patrones de sensibilidad colateral robustos que permitan el diseño de nuevas estrategias terapéuticas basadas en el uso de antibióticos con los que ya contamos a día de hoy.

Más información

S Hernando-Amado, P Laborda, JR Valverde,  JL Martínez. Mutational background influences Pseudomonas aeruginosa ciprofloxacin resistance evolution but preserves collateral sensitivity robustness, Proceedings of the National Academy of Sciences 2022;

 DOI: https://doi.org/10.1073/pnas.2109370119

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