E Recacha1, J Machuca1, S Díaz-Díaz2,3,4, A García-Duque1, M Ramos-Guelfo1, F Docobo-Pérez2,3,4, J Blázquez5, A Pascual1,2,3,4, J M Rodríguez-Martínez2,3,4. 1. Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen Macarena, Seville, Spain. 2. Departamento de Microbiología, Facultad de Medicina, Universidad de Sevilla, Seville, Spain. 3. Red Española de Investigación en Patología Infecciosa (REIPI), Instituto de Salud Carlos III, Madrid, Spain. 4. Instituto de Biomedicina de Sevilla IBIS, Hospital Universitario Virgen Macarena/CSIC/Departamento de Microbiología, Universidad de Sevilla, Seville, Spain. 5. Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
Abstract
Background: Suppression of the SOS response has been proposed as a therapeutic strategy for potentiating quinolones against susceptible, low-level quinolone-resistant (LLQR) and resistant Enterobacteriaceae. Objectives: To monitor the functionality of the SOS response in the evolution towards clinical quinolone resistance and study its impact on the evolution of spatiotemporal resistance. Methods: An isogenic collection of Escherichia coli (derived from the strain ATCC 25922) carrying combinations of chromosomally and plasmid-mediated quinolone resistance mechanisms (including susceptible, LLQR and resistant phenotypes) and exhibiting a spectrum of SOS activity was used. Relevant clinical parameters such as mutation rate, mutant prevention concentration (MPC), bacterial fitness, biofilm formation and post-antibiotic effect (PAE) were evaluated. Results: Inactivating the SOS response (recA deletion) led to a decrease in mutation rate (∼103 fold) in LLQR compared with WT strains at ciprofloxacin concentrations of 1 mg/L (the EUCAST breakpoint for resistance) and 2.5 mg/L (Cmax), as well as a remarkable delay in the spatiotemporal evolution of quinolone resistance. For all strains, there was an 8-fold decrease in MPC in RecA-deficient strains, with values for LLQR strains decreasing below the Cmax of ciprofloxacin. Inactivation of the SOS response reduced competitive fitness by 33%-50%, biofilm production by 22%-80% and increased the PAE by ∼3-4 h at sub-MIC concentrations of ciprofloxacin. Conclusions: Our data indicate that suppression of the SOS response affects key bacterial traits and is a promising strategy for reversing and tackling the evolution of antibiotic resistance in E. coli, including low-level and resistant phenotypes at therapeutic quinolone concentrations.
Background: Suppression of the SOS response has been proposed as a therapeutic strategy for potentiating quinolones against susceptible, low-level quinolone-resistant (LLQR) and resistant Enterobacteriaceae. Objectives: To monitor the functionality of the SOS response in the evolution towards clinical quinolone resistance and study its impact on the evolution of spatiotemporal resistance. Methods: An isogenic collection of Escherichia coli (derived from the strain ATCC 25922) carrying combinations of chromosomally and plasmid-mediated quinolone resistance mechanisms (including susceptible, LLQR and resistant phenotypes) and exhibiting a spectrum of SOS activity was used. Relevant clinical parameters such as mutation rate, mutant prevention concentration (MPC), bacterial fitness, biofilm formation and post-antibiotic effect (PAE) were evaluated. Results: Inactivating the SOS response (recA deletion) led to a decrease in mutation rate (∼103 fold) in LLQR compared with WT strains at ciprofloxacin concentrations of 1 mg/L (the EUCAST breakpoint for resistance) and 2.5 mg/L (Cmax), as well as a remarkable delay in the spatiotemporal evolution of quinolone resistance. For all strains, there was an 8-fold decrease in MPC in RecA-deficient strains, with values for LLQR strains decreasing below the Cmax of ciprofloxacin. Inactivation of the SOS response reduced competitive fitness by 33%-50%, biofilm production by 22%-80% and increased the PAE by ∼3-4 h at sub-MIC concentrations of ciprofloxacin. Conclusions: Our data indicate that suppression of the SOS response affects key bacterial traits and is a promising strategy for reversing and tackling the evolution of antibiotic resistance in E. coli, including low-level and resistant phenotypes at therapeutic quinolone concentrations.
Authors: S Diaz-Diaz; E Recacha; J Machuca; A García-Duque; F Docobo-Pérez; J Blázquez; A Pascual; J M Rodríguez-Martínez Journal: Antimicrob Agents Chemother Date: 2021-03-18 Impact factor: 5.191
Authors: Ana Victoria Cheng Jaramillo; Michael B Cory; Allen Li; Rahul M Kohli; William M Wuest Journal: Bioorg Med Chem Lett Date: 2022-03-26 Impact factor: 2.940