Journal of Antimicrobial Chemotherapy 2018 (In press)
This study was coordinated at University Hospital Virgen Macarena in collaboration with the Centro Nacional de Biotecnología. This work shows that suppression of the SOS response (through recA deleted) blocks the evolution towards clinical quinolone resistance across a range of E. coli phenotypes from highly susceptible to highly resistant, and plays a significant role in preventing mutagenesis events so increasing the activity of these bactericidal drugs against bacteria with multiple mechanisms of acquired resistance. The development of RecA inhibitors could function as an adjuvant therapy, potentiating antimicrobial activity and contributing to the slowdown on the emergence of mutants in low-level quinolone-resistant E. coli.
Suppression of the SOS response has been postulated as a therapeutic strategy for potentiating of antimicrobials. We aimed to evaluate the impact of its suppression in the blocking of the evolution towards resistance using a model of isogenic strains of E. coli representing multiple levels of quinolone resistance. E. coli mutants, exhibiting a spectrum of SOS activity, were constructed from isogenic strains carrying quinolone resistance mechanisms with susceptible and resistance phenotypes. Suppression of the SOS response led to a decrease in mutation rate (~103 fold) in LLQR at clinical relevant concentrations of ciprofloxacin, as well as a remarkable delay in the spatiotemporal evolution of quinolone resistance. For all strains, there was an 8-fold decrease in MPC, with values for LLQR strains decreasing below the Cmax of ciprofloxacin. A reduction of the fitness (33-50%) and the biofilm production (22-80%) were observed, and an increased PAE by around 3-4 hours was also induced after SOS suppression in LLQR srains.
Resumen en español
El rápido incremento de patógenos resistentes a la mayoría de antimicrobianos de uso habitual en clínica se ha proclamado como un problema de salud pública mundial. Son necesarias nuevas estrategias para bloquear el desarrollo de la resistencia y prolongar la vida de los antibióticos. La respuesta SOS se considera una prometedora diana para el desarrollo de nuevos compuestos que impidan la evolución de las bacterias hacia la resistencia, mejorando la actividad bactericida de agentes antimicrobianos como las quinolonas. Con este objetivo, hemos generado una colección de E. coli mutantes cubriendo el espectro de actividad de la respuesta SOS, que van desde una respuesta natural SOS a una respuesta hipo-inducible o constitutivamente suprimida. En este trabajo se pone de manifiesto su impacto sobre el bloqueo de la emergencia de mutantes resistentes y el retraso de la evolución espacio temporal de la resistencia a quinolonas, así como su capacidad para reducir la virulencia bacteriana, en un conjunto de cepas isogénicas que llevan diferentes combinaciones de mecanismos de resistencia con fenotipos de sensibilidad disminuida, resistentes y altamente resistentes. Nuestro análisis muestra que la supresión de la respuesta SOS podría ser una estrategia eficiente en la restricción de la emergencia de mutantes, posibilitando la utilización de antimicrobianos en desuso.
Blázquez, A. Pascual, J.M. Rodríguez-Martínez.
E. Recacha, J. Machuca, S. Díaz-Díaz, A. García-Duque, M. Ramos-Guelfo, F. Docobo-Pérez, J. Blázquez, A. Pascual, J.M. Rodríguez-Martínez.
Unidad de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen Macarena, Seville, Spain; Departamento de Microbiología, Universidad de Sevilla, Sevilla, Spain; Red Española de Investigación en Patología Infecciosa (REIPI), Instituto de Salud Carlos III, Madrid, Spain; Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain; Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
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