Fast Evolution of SOS-Independent Multi-Drug Resistance in Bacteria
user-61447a76e55422cecdaf7d19(2022)
Abstract
AbstractThe killing mechanism of many antibiotics involves the induction of DNA damage, either directly or indirectly, which triggers the SOS response. RecA, the master regulator of the SOS response, plays a crucial role in driving the evolution of resistance to fluoroquinolone antibiotics treated with a single dose of ciprofloxacin. However, the precise roles of RecA and SOS responses in the development of resistance under short-term β-lactam exposure remain unclear. In the present study, we observed a fast evolution of β-lactam resistance (20-fold increase in MIC in 8 hours) inE. coliafter deleting RecA and exposing the bacteria to a single dose of ampicillin. Notably, once this type of resistance is established, it remains stable and can be passed on to subsequent generations. Contrary to previous findings, it is shown that this accelerated resistance development process is dependent on the hindrance of DNA repair, which is completely orthogonal to the SOS response. Additionally, we identified the rapid emergence of drug resistance associated mutations in the resistant bacterial genome, indicating the impairment of DNA repair. Through comprehensive transcriptome sequencing, we discovered that the expression of numerous antioxidative response genes is repressed inrecAmutant resistant isolates, resulting in an excessive accumulation of ROS within the cells. This suggests that the induction of ROS drives the fast evolution of antibiotic resistance in RecA-deficient bacteria. Collectively, we show that the hindrance of DNA repair hampers cellular fitness, provides bacteria with genetic adaptability to survive in diverse stressful environments, and accelerates the evolution of antibiotic resistance.
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