Effect of RecA inactivation on quinolone susceptibility and the evolution of resistance in clinical isolates of Escherichia coli

Background: SOS response suppression (by RecA inactivation) has been postulated as a therapeutic strategy for potentiating antimicrobials against Enterobacterales. Objectives: To evaluate the impact of RecA inactivation on the reversion and evolution of quinolone resistance using a collection of Escherichia coli clinical isolates. Methods: Twenty-three E. coli clinical isolates, including isolates belonging to the high-risk clone ST131, were included. SOS response was suppressed by recA inactivation. Susceptibility to fluoroquinolones was determined by broth microdilution, growth curves and killing curves. Evolution of quinolone resistance was evaluated by mutant frequency and mutant prevention concentration (MPC). Results: RecA inactivation resulted in 2-16-fold reductions in fluoroquinolone MICs and modified EUCAST clinical category for several isolates, including ST131 clone isolates. Growth curves and time-kill curves showed a clear disadvantage (up to 10 Log(10) cfu/mL after 24 h) for survival in strains with an inactivated SOS system. For recA-deficient mutants, MPC values decreased 4-8-fold, with values below the maximum serum concentration of ciprofloxacin. RecA inactivation Led to a decrease in mutant frequency (>= 10(3)-fold) compared with isolates with unmodified SOS responses at ciprofloxacin concentrations of 4xMIC and 1 mg/L. These effects were also observed in ST131 clone isolates. Conclusions: While RecA inactivation does not reverse existing resistance, it is a promising strategy for increasing the effectiveness of fluoroquinolones against susceptible clinical isolates, including high-risk clone isolates.

Automated summary

RecA inactivation leads to decreased fluoroquinolone resistance in Escherichia coli clinical isolates, especially in high-risk clone ST131. Inactivation of the SOS system results in a survival disadvantage for E. coli, reducing the development of quinolone resistance.