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Quinolone Resistance Reversion by Targeting the SOS Response
E Recacha1,2, J Machuca1,3,4, P Díaz de Alba1
1Unidad de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen Macarena, Seville, Spain.
Mbio
|October 12, 2017
Summary
Suppressing the SOS response in Escherichia coli resensitizes bacteria to quinolone antibiotics, even those with multiple resistance mechanisms. This strategy significantly enhances antibiotic efficacy in vivo, offering a new approach to combatting antimicrobial resistance.
Area of Science:
- Microbiology and Infectious Diseases
- Molecular Biology
- Pharmacology
Background:
- Antibiotic resistance is a critical global health threat, necessitating novel therapeutic strategies.
- The SOS response in bacteria is a DNA damage repair mechanism that can contribute to antibiotic resistance.
- Targeting the SOS response is a potential strategy to potentiate antimicrobial agents and reverse resistance.
Purpose of the Study:
- To evaluate the impact of suppressing the SOS response on reversing quinolone resistance in Escherichia coli.
- To assess the effectiveness of SOS response suppression in enhancing antimicrobial agent efficacy in vitro and in vivo.
Main Methods:
- Construction of isogenic E. coli strains with varying levels of SOS activity and quinolone resistance mechanisms.
- Evaluation of changes in susceptibility using minimum inhibitory concentrations (MICs) and dynamic killing assays (killing curves, flow cytometry).
- Assessment of in vivo efficacy using a murine peritoneal sepsis model with ciprofloxacin.
Main Results:
- Suppression of the SOS response resensitized E. coli strains with multiple resistance mechanisms, showing up to 15-fold reductions in MICs.
- Killing curve assays demonstrated a significant survival disadvantage for bacteria with a suppressed SOS response (8 log units reduction).
- In vivo efficacy of ciprofloxacin was significantly enhanced in resistant strains with suppressed SOS response (1.76 log units reduction).
Conclusions:
- Suppression of the SOS response effectively reverses antimicrobial resistance in E. coli across a spectrum of resistance levels.
- This strategy significantly enhances the in vivo efficacy of quinolone antibiotics like ciprofloxacin.
- Targeting the SOS response presents a promising new therapeutic strategy for combating antibiotic-resistant bacterial infections.
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