Lipid-lowering drug clofibric acid promotes conjugative transfer of RP4 plasmid carrying antibiotic resistance genes by multiple mechanisms

Antibiotic resistance represents a growing global health crisis, predominantly driven by the selective pressure imposed by antibiotics, which facilitates horizontal gene transfer. However, the potential role of non-antibiotic pharmaceuticals in promoting or enabling the spread of antibiotic resistance genes (ARGs) remains poorly understood. This study provided novel insights into the capacity of clofibric acid, a lipid-lowering drug, to enhance the conjugative transfer of ARGs, and deeply explored the underlying multiple mechanisms. The findings revealed that clofibric acid, at concentrations ranging from 0.01 to 1000 mu g/L, significantly promoted the transfer efficiency of the RP4 plasmid carrying multiple ARGs. This enhancement was accompanied by a cascade of stress responses in bacterial cells, including elevated production of reactive oxygen species, increased secretion of extracellular polymeric substances, reduced bacterial surface zeta potential, and heightened cell membrane permeability. The physiological alterations were closely linked to significant changes in the expression of genes associated with these processes. Our results highlighted the potential of non-antibiotic pharmaceuticals to contribute to the dissemination of antibiotic resistance, offering a critical foundation for further research into the environmental and public health implications of such compounds.