The Atypical Antipsychotic Quetiapine Promotes Multiple Antibiotic Resistance in Escherichia coli

Yasuhiro Kyono, Lori Ellezian, Yue Yue Hu, Kanella Eliadis, Junlone Moy, Elizabeth B. Hirsch, Michael J. Federle, Stephanie A. Flowers

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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.

Original languageEnglish (US)
JournalJournal of bacteriology
Volume204
Issue number5
DOIs
StatePublished - May 2022

Bibliographical note

Funding Information:
Editor George O'Toole, Geisel School of Medicine at Dartmouth Copyright © 2022 American Society for Microbiology. All Rights Reserved. Address correspondence to Stephanie A. Flowers, [email protected]. The authors declare a conflict of interest. E.B.H. has received grant funding from Merck and advisory board honoraria from Merck, MeMed, and Melinta. Received 14 March 2022 Accepted 15 March 2022 Published 13 April 2022

Publisher Copyright:
© 2022 American Society for Microbiology.

Keywords

  • antimicrobial resistance
  • atypical antipsychotics
  • Microbial Sensitivity Tests
  • Escherichia coli Infections/drug therapy
  • Quetiapine Fumarate/pharmacology
  • Antipsychotic Agents/pharmacology
  • Humans
  • Escherichia coli Proteins/genetics
  • Escherichia coli/genetics
  • Anti-Bacterial Agents/pharmacology
  • Drug Resistance, Microbial/genetics
  • Repressor Proteins/genetics

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article

Fingerprint

Dive into the research topics of 'The Atypical Antipsychotic Quetiapine Promotes Multiple Antibiotic Resistance in Escherichia coli'. Together they form a unique fingerprint.

Cite this