Nonantibiotic Pharmaceuticals Exhibit Antibacterial Activity and Enhance Bacterial Evolution toward Antibiotic Resistance

Nonantibiotic pharmaceuticals are widely used to treat various human diseases and can also be ubiquitously detected as emerging contaminants in the environment, thus coexisting with various environmental bacteria. Previous studies have shown that several nonantibiotic pharmaceuticals can trigger mutation and promote horizontal transfer of antibiotic resistance genes between bacteria. However, it is still unclear whether nonantibiotic pharmaceuticals have an antibiotic-like antimicrobial activity against environmental bacteria. In this study, we investigated the antimicrobial effects of four typical nonantibiotic pharmaceuticals (gemfibrozil, ibuprofen, propranolol, and sertraline) against environmental bacteria and the evolution of bacterial antibiotic resistance when challenged with these nonantibiotic pharmaceuticals. Surprisingly, all four pharmaceuticals exhibit antibacterial activity through a mechanism similar to that of antibiotics. They can increase reactive oxygen species production and enhance membrane permeability up to 2.7- and 2.4-fold, respectively. The expressions of sodA, sodB, and recA genes related to reactive oxygen species detoxification and SOS response were upregulated. We also found that these pharmaceuticals can upregulate the expression of the efflux pump gene tolC with 2.5-fold to promote the evolution of bacterial antibiotic resistance. This study provides insights into the role of nonantibiotic pharmaceuticals in the emergence of antibiotic resistance and highlights the negative effects of nonantibiotic pharmaceuticals on environmental bacteria.