The role of oxidative stress in development of antimicrobial resistance in E. coli

Antibiotics are extensively utilized in the veterinary sector for various applications, including treatment and prevention of microbial infections, as well as the promotion of livestock growth in various low- and middle-income countries. As a result, more antibiotics are used to treat animals than to treat human disease. This widespread use of antibiotics causes the emergence and dissemination of resistance among veterinary or environmental microorganisms. In response to antibiotic-induced stress, bacteria activate various general or specific responses, leading to physiological adaptations, genetic mutations, and the acquisition of exogenous genes, resulting in the development of resistance. This study investigates whether bacterial stress responses, particularly oxidative stress and stringent responses, influence the de novo acquisition of antimicrobial resistance through genetic mutations. Our findings demonstrate that reactive oxygen species (ROS) under aerobic conditions and reactive metabolic byproducts under anaerobic conditions accelerate the de novo acquisition of antibiotic resistance in E. coli by activating the SOS response, consequently initiating DNA damage-repair mutagenesis. Additionally, the knockout of (p)ppGpp synthetase RelA impedes the acquisition of resistance to bactericidal antibiotics by lowering growth rate and ROS production. Both oxidative stress and stringent responses play pivotal roles in de novo acquisition of antimicrobial resistance. Furthermore, our study reveals that oxidative stress and stringent responses exert notable influence on the fitness costs associated with resistance development. This study provides important theoretical support for a comprehensive understanding of the mechanisms by which antibiotics acquire de novo resistance to identify potential drug targets and advance the development of new antibiotic candidates and adjuvants.