Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen Macarena, Seville, Spain.
Red Española de Investigación en Patología Infecciosa (REIPI), Instituto de Salud Carlos III, Madrid, Spain.
J Antimicrob Chemother. 2021 Jan 19;76(2):338-344. doi: 10.1093/jac/dkaa448.
SOS response suppression (by RecA inactivation) has been postulated as a therapeutic strategy for potentiating antimicrobials against Enterobacterales.
To evaluate the impact of RecA inactivation on the reversion and evolution of quinolone resistance using a collection of Escherichia coli clinical isolates.
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).
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 log10 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 (≥103-fold) compared with isolates with unmodified SOS responses at ciprofloxacin concentrations of 4×MIC and 1 mg/L. These effects were also observed in ST131 clone isolates.
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.
已提出 SOS 反应抑制（通过 RecA 失活）作为增强抗 Enterobacterales 抗菌药物作用的治疗策略。
使用一系列大肠杆菌临床分离株评估 RecA 失活对喹诺酮类耐药性回复和进化的影响。
纳入 23 株大肠杆菌临床分离株，包括属于高风险克隆 ST131 的分离株。通过 RecA 失活抑制 SOS 反应。通过肉汤微量稀释法、生长曲线和杀菌曲线来确定对氟喹诺酮类药物的敏感性。通过突变频率和突变预防浓度（MPC）来评估喹诺酮类耐药性的进化。
RecA 失活导致几种分离株（包括 ST131 克隆分离株）的氟喹诺酮 MIC 值降低 2-16 倍，并且改变了 EUCAST 临床分类。生长曲线和时间杀伤曲线显示，在 SOS 系统失活的菌株中，生存具有明显的劣势（24 小时后多达 10log10 cfu/mL）。对于缺乏 RecA 的突变体，MPC 值降低了 4-8 倍，其值低于环丙沙星的最大血清浓度。与未修饰的 SOS 反应相比，RecA 失活导致在环丙沙星浓度为 4×MIC 和 1mg/L 时，突变频率降低（≥103 倍）。这些效应在 ST131 克隆分离株中也观察到。
虽然 RecA 失活不能逆转现有的耐药性，但它是提高氟喹诺酮类药物对敏感临床分离株（包括高风险克隆分离株）有效性的有前途的策略。
