Unidad de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen Macarena, Seville, Spain.
Departamento de Microbiología, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain.
J Antimicrob Chemother. 2022 Feb 23;77(3):641-645. doi: 10.1093/jac/dkab445.
Suppression of SOS response and overproduction of reactive oxygen species (ROS) through detoxification system suppression enhance the activity of fluoroquinolones.
To evaluate the role of both systems in the evolution of resistance to ciprofloxacin in an isogenic model of Escherichia coli.
Single-gene deletion mutants of E. coli BW25113 (wild-type) (ΔrecA, ΔkatG, ΔkatE, ΔsodA, ΔsodB), double-gene (ΔrecA-ΔkatG, ΔrecA-ΔkatE, ΔrecA-ΔsodA, ΔrecA-ΔsodB, ΔkatG-ΔkatE, ΔsodB-ΔsodA) and triple-gene (ΔrecA-ΔkatG-ΔkatE) mutants were included. The response to sudden high ciprofloxacin pressure was evaluated by mutant prevention concentration (MPC). The gradual antimicrobial pressure response was evaluated through experimental evolution and antibiotic resistance assays.
For E. coli BW25113 strain, ΔkatE, ΔsodB and ΔsodB/ΔsodA mutants, MPC values were 0.25 mg/L. The ΔkatG, ΔsodA, ΔkatG/katE and ΔrecA mutants showed 2-fold reductions (0.125 mg/L). The ΔkatG/ΔrecA, ΔkatE/ΔrecA, ΔsodA/ΔrecA, ΔsodB/ΔrecA and ΔkatG/ΔkatE/ΔrecA strains showed 4-8-fold reductions (0.03-0.06 mg/L) relative to the wild-type. Gradual antimicrobial pressure increased growth capacity for ΔsodA and ΔsodB and ΔsodB/ΔsodA mutants (no growth in 4 mg/L) compared with the wild-type (no growth in the range of 0.5-2 mg/L). Accordingly, increased growth was observed with the mutants ΔrecA/ΔkatG (no growth in 2 mg/L), ΔrecA/ΔkatE (no growth in 2 mg/L), ΔrecA/ΔsodA (no growth in 0.06 mg/L), ΔrecA/ΔsodB (no growth in 0.25 mg/L) and ΔrecA/ΔkatG/ΔkatE (no growth in 0.5 mg/L) compared with ΔrecA (no growth in the range of 0.002-0.015 mg/L).
After RecA inactivation, gradual exposure to ciprofloxacin reduces the evolution of resistance. After suppression of RecA and detoxification systems, sudden high exposure to ciprofloxacin reduces the evolution of resistance in E. coli.
通过抑制解毒系统来抑制 SOS 反应和活性氧物质（ROS）的过度产生，可增强氟喹诺酮类药物的活性。
在大肠杆菌的同源模型中评估这两个系统在环丙沙星耐药性演变中的作用。
包括大肠杆菌 BW25113（野生型）（ΔrecA、ΔkatG、ΔkatE、ΔsodA、ΔsodB）的单基因突变体、双基因突变体（ΔrecA-ΔkatG、ΔrecA-ΔkatE、ΔrecA-ΔsodA、ΔrecA-ΔsodB、ΔkatG-ΔkatE、ΔsodB-ΔsodA）和三基因突变体（ΔrecA-ΔkatG-ΔkatE）。通过突变预防浓度（MPC）评估对突然高浓度环丙沙星压力的反应。通过实验进化和抗生素耐药性测定评估逐渐的抗菌压力反应。
对于大肠杆菌 BW25113 菌株，ΔkatE、ΔsodB 和 ΔsodB/ΔsodA 突变体的 MPC 值为 0.25mg/L。ΔkatG、ΔsodA、ΔkatG/katE 和 ΔrecA 突变体的浓度降低了 2 倍（0.125mg/L）。与野生型相比，ΔkatG/ΔrecA、ΔkatE/ΔrecA、ΔsodA/ΔrecA、ΔsodB/ΔrecA 和 ΔkatG/ΔkatE/ΔrecA 菌株的浓度降低了 4-8 倍（0.03-0.06mg/L）。与野生型相比（在 0.5-2mg/L 范围内无生长），逐渐增加的抗菌压力增加了 ΔsodA 和 ΔsodB 以及 ΔsodB/ΔsodA 突变体的生长能力（在 4mg/L 时无生长）。相应地，与ΔrecA（在 0.002-0.015mg/L 范围内无生长）相比，突变体ΔrecA/ΔkatG（在 2mg/L 时无生长）、ΔrecA/ΔkatE（在 2mg/L 时无生长）、ΔrecA/ΔsodA（在 0.06mg/L 时无生长）、ΔrecA/ΔsodB（在 0.25mg/L 时无生长）和ΔrecA/ΔkatG/ΔkatE（在 0.5mg/L 时无生长）的生长能力增加。
RecA 失活后，逐渐接触环丙沙星可降低耐药性的进化。抑制 RecA 和解毒系统后，大肠杆菌突然接触高浓度环丙沙星可降低耐药性的进化。
