The Role of Intracellular ROS in the Development of Antimicrobial Resistance:A Convergent Mediator Linking Mutations and Horizontal Gene Transfer.

The development of antimicrobial resistance (AMR) is a major threat to global public health and environmental security. While antibiotics are known drivers, a wide range of non-antibiotic pollutants also promote antibiotic resistance genes (ARG) dissemination, yet the underlying unifying mechanism remains poorly integrated. This paper systematically analyzes how reactive oxygen species (ROS) act as major convergent mediator that drive the evolution of ARGs by promoting mutation and horizontal gene transfer (HGT) under various environmental stress conditions. The mechanisms of antibiotic-induced ROS generation and the controversial role of ROS in bacterial lethality are first delineated. It is then revealed that numerous non-antibiotic stressors, including disinfectants, heavy metals, nanoparticles, pharmaceuticals, and organic pollutants, convergently promote ARG conjugation, transformation, and transduction. Within these processes, moderate levels of intracellular ROS promote ARG dissemination, whereas excessive oxidative stress inhibits transfer or compromises cell viability. Based on these observations, we propose the concept of an "oxidative window" to describe the bidirectional regulatory effect of ROS on ARG dissemination at different concentrations. Furthermore , strategies to suppress ARG spread by modulating intracellular ROS are discussed, shifting from total elimination to precise regulation within the permissive window. Building upon this mechanistic framework, we further discuss the potential of incorporating ROS-related metrics into machine-learning-assisted risk assessment models and evaluate emerging ROS-regulation strategies for mitigating ARG dissemination. By reframing ROS from a passive byproduct into a measurable and potentially predictive indicator of ARG dissemination risk, this review provides a new conceptual basis for predicting and controlling environmental resistance risks.