Systematically Altering Bacterial SOS Activity under Stress Reveals Therapeutic Strategies for Potentiating...

Area of Science:

• Microbiology
• Bacterial genetics
• Drug resistance

Background:

• The bacterial SOS response is a DNA repair network crucial for survival and acquired drug resistance under antimicrobial stress.
• LexA and RecA are key regulators of the SOS response, making them potential targets for adjuvant therapies against antibiotic resistance.
• Uncertainty remains regarding the optimal strategy for targeting the SOS response, including whether hyperactivation is beneficial or which regulator (LexA or RecA) is a better target.

Purpose of the Study:

• To comprehensively assess the impact of modulating SOS response activity on bacterial susceptibility to various antimicrobials.
• To determine the relative efficacy of targeting LexA versus RecA for combating antibiotic resistance.
• To identify optimal antimicrobial partners for SOS-targeting adjuvant therapies.

Main Methods:

• Generated Escherichia coli strains with mutations in lexA or recA to achieve a full spectrum of SOS activity levels.
• Systematically analyzed the effects of various antimicrobials on these strains by measuring mean inhibitory concentrations (MICs) and induced mutation rates.
• Compared the impact of repressed versus hyperactivated SOS responses on antimicrobial efficacy.

Main Results:

• Significant changes in MICs were primarily observed with DNA-damaging antibiotics, with repressed SOS responses showing greater susceptibility.
• Antibiotic-induced mutation rates were suppressed across a broader range of antibiotics when SOS activity was reduced.
• Targeting either LexA or RecA demonstrated comparable viability as strategies for modulating the SOS response.

Conclusions:

• Perturbing the SOS response, by targeting either LexA or RecA, is a viable strategy to increase bacterial susceptibility and reduce mutagenesis.
• Combining SOS inhibitors with DNA-damaging antibiotics may be the most effective approach for lowering MICs and decreasing acquired drug resistance.
• This study provides evidence supporting multiple adjuvant strategies for combating antibiotic resistance by targeting the bacterial SOS pathway.