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

Abstract

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 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. We systematically investigated the underlying mechanisms by which clofibric acid stimulates this process, with a focus on its effects on critical stages of bacterial conjugation. Our findings reveal that clofibric acid, at concentrations ranging from 0.01 to 1000 μg/L, significantly enhances the transfer efficiency of the RP4 plasmid, which carries multiple antibiotic resistance genes. This enhancement is 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. These physiological alterations are closely linked to significant changes in the expression of genes associated with these processes. Our results highlight 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.