Atypical antipsychotic (AAP) medication is a critical tool for treating symptoms of psychiatric disorders. While AAPs primarily target dopamine (D2) and serotonin (5HT2A and 5HT1A) receptors, they also exhibit intrinsic antimicrobial activity as an off-target effect. Because AAPs are often prescribed to patients for many years, a potential risk associated with long-term AAP use is the unintended emergence of bacteria with antimicrobial resistance (AMR). Here, we show that exposure to the AAP quetiapine at estimated gut concentrations promotes AMR in Escherichia coli after 6 weeks. Quetiapine-exposed isolates exhibited an increase in MICs for ampicillin, tetracycline, ceftriaxone, and levofloxacin. By whole-genome sequencing analysis, we identified mutations in genes that confer AMR, including the repressor for the multiple antibiotic resistance mar operon (marR), and real-time reverse transcription-quantitative PCR (RT-qPCR) analysis showed increased levels of marA, acrA, and tolC mRNAs and reduced levels of ompF mRNA in the isolates carrying marR mutations. To determine the contribution of each marR mutation to AMR, we constructed isogenic strains carrying individual mutant marR alleles in the parent background and reevaluated their resistance phenotypes using MIC and RT-qPCR assays. While marR mutations induced robust activity of the mar operon, they resulted in only modest increases in MICs. Interestingly, although these marR mutations did not fully recapitulate the AMR phenotype of the quetiapine-exposed isolates, we show that marR mutations promote growth fitness in the presence of quetiapine. Our findings revealed an important link between the use of AAPs and AMR development in E. coli. IMPORTANCE AAP medication is a cornerstone in the treatment of serious psychiatric disease. The AAPs are known to exhibit antimicrobial activity; therefore, a potential unintended risk of long-term AAP use may be the emergence of AMR, although such risk has received little attention. In this study, we describe the development of multidrug antibiotic resistance in Escherichia coli after 6 weeks of exposure to the AAP quetiapine. Investigation of mutations in the marR gene, which encodes a repressor for the multiple antibiotic resistance (mar) operon, reveals a potential mechanism that increases the fitness of E. coli in the presence of quetiapine. Our findings establish a link between the use of AAPs and AMR development in bacteria.

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