Decoding Quetiapine's Impact: Antibiotic Efflux, Cell Membrane and Cell Wall Synthesis Genes in the Mouse Fecal Resistome

Abstract Background: As the understanding of antimicrobial activity exerted by non-antibiotic pharmaceuticals continues to evolve, the implications for antimicrobial resistance (AMR) in gut bacteria have garnered significant interest. Quetiapine, a commonly prescribed second-generation antipsychotic (SGA) drug, has been implicated in this context. Our prior research has shown that quetiapine contributes to AMR in vitro; however, the exact mechanism and impact of this interaction are unclear. In this study, we aimed to understand the impact of quetiapine on the gut resistome of C57BL/6NHsd adult male and female mice. Methods: Mice were exposed to quetiapine via drinking water over a 12-week period, and the fecal resistome was assessed longitudinally and compared to a parallel control group that received regular drinking water. Given that AMR genes comprise a small fraction of a metagenome, we utilized a hybrid capture approach to survey longitudinal dynamics of AMR genes and gene variants. Further, we evaluated the minimal inhibitory concentrations of Escherichia coli exposed to quetiapine in vitro as well as isolates cultured from mouse stool to assess changes in antibiotic susceptibility. Results: We found that quetiapine exposure increased the relative abundance of AMR gene families related to antibiotic efflux, the phosphoethanolamine transferases, and undecaprenyl pyrophosphate-related proteins in the mouse fecal resistome. Consistent with these findings, E. coli isolates, cultured from mice exposed to quetiapine, displayed a significant decrease in sensitivity to colistin when compared to E. colicultured from control mice naive to quetiapine. Conclusion: This study provides the first evidence that quetiapine, and possibly other SGAs, could contribute to AMR development in complex microbial communities in vivo. These findings underline the importance of further research into the effects of psychiatric medication on the gut resistome to inform more effective clinical practice and antimicrobial stewardship.