Making waves: The overlooked role of non-antibiotic drugs in driving antibiotic resistance gene dissemination.

Antibiotic resistance gene (ARG) dissemination has long been attributed primarily to antibiotic contamination. However, this paradigm is increasingly challenged by emerging evidence that non antibiotic drugs (NADs) constitute a pervasive and previously overlooked driver of ARG spread. Here, we summarize that widely-used NADs (such as antidepressants and non-steroidal anti-inflammatory drugs) can actively promote horizontal gene transfer (HGT) and accelerate the emergence of multidrug resistance within microbial communities. Notably, significant enhancement of ARG dissemination has been reported even at clinically or environmentally relevant concentrations (e.g., 0.005-0.05 mg/L) commonly detected in wastewater and aquatic systems, by inducing stress responses in bacteria. The stress consequently elevated reactive oxygen species production, increased membrane permeability, and activation of efflux systems, collectively facilitating ARG mobility and persistence. These findings suggest that the ecological risks associated with NADs extend beyond conventional toxicity concerns and into the realm of antimicrobial resistance evolution. To address this emerging challenge, we propose several paradigm-shifting strategies to reduce relevant environmental risk of NADs, including molecular-level risk prediction based on chemical properties, artificial intelligence-assisted drug design, engineered microbial degradation systems, and advanced wastewater treatment technologies. Recognizing and mitigating NAD-driven ARG dissemination is essential for safeguarding environmental and public health in the post-antibiotic era.