The Atypical Antipsychotic Quetiapine Promotes Multiple Antibiotic Resistance in Escherichia coli

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

doi:10.1128/jb.00102-22

Cited by 15 publications

(13 citation statements)

References 55 publications

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“…Interestingly, while our previous in vitro study demonstrated clinical resistance to ampicillin, ceftriaxone, and a 16-fold increase in MICs to levo oxacin following six weeks of exposure to quetiapine at gutrelevant concentrations (10mg/L (Isolates A-C) or 100 mg/L(Isolates D-F)) 12 , the E.coli isolates cultured from the mouse stool showed no such statistically signi cant increase in susceptibility (Supplemental Fig. 3).…”

Section: Mobile Genetic Elements (Mges) Linked To Quetiapine Exposurementioning

confidence: 79%

“…Transitioning from these clinical observations to a more controlled experimental setting, we sought to emulate the potential impact of quetiapine on the gut microbiota. In our previous investigations, we found that E. coli developed MDR after six weeks of in vitro exposure to quetiapine, even at concentrations that were four-fold lower than those estimated in the human colon, and whole-genome sequencing analysis of quetiapine-exposed isolates revealed mutations in known AMR genes 12 . Based on these ndings, we hypothesized that chronic exposure of bacteria to SGAs such as quetiapine over time can indirectly select for AMR mechanisms in the gut microbial community of patients who often necessitate years of quetiapine treatment.…”

Section: Introductionmentioning

confidence: 85%

“…Euclidean distance matrix was computed using the log-transformed normalized gene count data. Permutational multivariate analysis of variance (PERMANOVA) was conducted using the adonis2 function in the vegan package in R 24 to test for signi cant differences in gene abundance between the baseline values and the 12 Isolating E. coli from stool: We isolated bacteria from frozen fecal samples as described by Ju and Willing 27 . Brie y, we added 1 mL of 1X Phosphate Buffered Saline (PBS) to the tube of frozen samples and incubated in the 37°C water bath for 5-10 min with occasional vortexing.…”

Section: Drug Administrationmentioning

confidence: 99%

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

Kyono,

Magboo,

Daley

et al. 2023

Preprint

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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.

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Section: Mobile Genetic Elements (Mges) Linked To Quetiapine Exposurementioning

confidence: 79%

Section: Introductionmentioning

confidence: 85%

Section: Drug Administrationmentioning

confidence: 99%

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

Kyono,

Magboo,

Daley

et al. 2023

Preprint

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show abstract

“…A key underexplored question that arises from these reciprocal drug–microbiome interactions is how they impact one another given the ability of microorganisms to evolve and change over short time scales within the host ( Zhao et al, 2019 ; Lieberman, 2022 ; Garud et al, 2019 ; Snitkin et al, 2013 ; Gatt and Margalit, 2021 ). Specifically, given that bacteria rapidly evolve resistance to antimicrobial drugs, it is plausible that adaptation to host-targeting drugs that are also antimicrobial will alter bacterial drug metabolism or its transport ( Rosener et al, 2020 ; Kyono et al, 2022 ). Such adaptions have been repeatedly observed with standard antibiotics ( Alekshun and Levy, 2007 ).…”

Section: Introductionmentioning

confidence: 99%

Evolved bacterial resistance to the chemotherapy gemcitabine modulates its efficacy in co-cultured cancer cells

Sayin

Rosener

et al. 2023

eLife

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Drug metabolism by the microbiome can influence anti-cancer treatment success. We previously suggested that chemotherapies with antimicrobial activity can select for adaptations in bacterial drug metabolism that can inadvertently influence the host's chemoresistance. We demonstrated that evolved resistance against fluoropyrimidine chemotherapy lowered its efficacy in worms feeding on drug-evolved bacteria (Rosener et al., 2020). Here we examine a model system that captures local interactions that can occur in the tumor microenvironment. Gammaproteobacteria colonizing pancreatic tumors can degrade the nucleoside-analog chemotherapy gemcitabine and, in doing so, can increase the tumor's chemoresistance. Using a genetic screen in Escherichia coli, we mapped all loss-of-function mutations conferring gemcitabine resistance. Surprisingly, we infer that one third of top resistance mutations increase or decrease bacterial drug breakdown and therefore can either lower or raise the gemcitabine load in the local environment. Experiments in three E. coli strains revealed that evolved adaptation converged to inactivation of the nucleoside permease NupC, an adaptation that increased the drug burden on co-cultured cancer cells. The two studies provide complementary insights on the potential impact of microbiome adaptation to chemotherapy by showing that bacteria-drug interactions can have local and systemic influence on drug activity.

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“…A key underexplored question that arises from these reciprocal drugmicrobiome interactions is how they impact one another given the ability of microorganisms to evolve and change over short time scales within the host [12][13][14][15][16] . Specifically, given that bacteria often rapidly evolve resistance to antimicrobial drugs, it is plausible that adaptation to hosttargeting drugs that are also antimicrobial will alter bacterial drug metabolism or its transport 17,18 . Such adaptions have been repeatedly observed with standard antibiotics 19 .…”

Section: Introductionmentioning

confidence: 99%

Evolved bacterial resistance to the chemotherapy gemcitabine modulates its efficacy

Sayin

Rosener

et al. 2022

Preprint

View full text Add to dashboard Cite

Drug metabolism by the microbiome can influence anti-cancer treatment success. We previously suggested that chemotherapies with antimicrobial activity can select for adaptations in bacterial drug metabolism that can inadvertently influence the host's chemoresistance. We demonstrated that evolved resistance against fluoropyrimidine chemotherapy lowered its efficacy in worms feeding on drug-evolved bacteria (Rosener et al., 2020). Here we examine a model system that captures local interactions that can occur in the tumor microenvironment. Gammaproteobacteria colonizing pancreatic tumors can degrade the nucleoside-analog chemotherapy gemcitabine and, in doing so, can increase the tumor's chemoresistance. Using a genetic screen in Escherichia coli, we mapped all loss-of-function mutations conferring gemcitabine resistance. Surprisingly, we found that one third of resistance mutations increase or decrease bacterial drug breakdown and therefore can either lower or raise the gemcitabine load in the local environment. Experiments in three E. coli strains revealed that evolved adaptation converged to inactivation of the nucleoside permease NupC, an adaptation that increased the drug burden on co-cultured cancer cells. The two studies provide complementary insights on the potential impact of microbiome adaptation to chemotherapy by showing that bacteria-drug interactions transpire locally and systemically and can influence chemoresistance in the host.

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The Atypical Antipsychotic Quetiapine Promotes Multiple Antibiotic Resistance in Escherichia coli

Abstract: 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.

Cited by 15 publications

References 55 publications

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

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

Evolved bacterial resistance to the chemotherapy gemcitabine modulates its efficacy in co-cultured cancer cells

Evolved bacterial resistance to the chemotherapy gemcitabine modulates its efficacy

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