Antipsychotic quetiapine alters the mouse fecal resistome by impacting antibiotic efflux, cell membrane, and cell wall synthesis genes

Abstract

ABSTRACT The understanding of the antimicrobial activities of non-antibiotic pharmaceuticals is evolving, with growing interest in their implications for antimicrobial resistance (AMR) in gut bacteria. Quetiapine, a frequently prescribed second-generation antipsychotic (SGA), is relevant in this context. While previous studies indicate quetiapine’s role in AMR development in vitro, the specific mechanisms and impacts remain undefined. We aim to elucidate quetiapine’s effects on the gut resistome in C57BL/6NHsd male and female mice. Over 12 weeks, mice received quetiapine in their drinking water. We longitudinally analyzed the fecal resistome, contrasting it with a control group receiving regular water. Recognizing AMR genes’ minute presence in metagenomes, we adopted a hybrid capture method to examine AMR genes’ longitudinal trends, correlating them with 16S ribosomal RNA (16S rRNA) sequencing data and validating with qPCR. We also evaluated the minimal inhibitory concentrations for Escherichia coli exposed to quetiapine in vitro and Escherichia species cultured from experimental mouse stool. Quetiapine exposure led to a pronounced increase in the relative abundance of certain AMR gene families within the mouse fecal resistome, notably those linked to antibiotic efflux, phosphoethanolamine transferases, and undecaprenyl pyrophosphate-related proteins. Escherichia isolates from quetiapine-exposed mice showed significantly reduced colistin sensitivity compared to isolates from control mice. Our findings mark the first evidence that quetiapine, and potentially other SGAs, may influence AMR evolution in complex in vivo microbial communities. This highlights the need for continued investigation into how medications impact the gut resistome, guiding improved clinical practices and antimicrobial stewardship. IMPORTANCE This study significantly contributes to our understanding of how certain medications can unintentionally contribute to a major global health issue, i.e., antibiotic resistance. Quetiapine, a widely used antipsychotic medication, was found to increase key resistance mechanisms of gut bacteria to antibiotics in mice. Specifically, these data suggest that quetiapine may target elements of the bacterial cell membrane. If similar effects are found in humans, this medicine could unexpectedly make it harder to treat certain infections. This research emphasizes the importance of being mindful about not just antibiotics themselves, but also about other medications that could inadvertently contribute to this problem. Ultimately, these findings underline the necessity for more in-depth research on the broader impact of pharmaceuticals.

Keywords

• antimicrobial resistance
• hybrid capture
• antipsychotics
• resistome