Resistance/fitness trade-off is a barrier to the evolution of MarR inactivation mutants in <i>Escherichia coli</i>

Alzrigat, Lisa Praski; Huseby, Douglas L.; Brandis, Gerrit; Hughes, Diarmaid

doi:10.1093/jac/dkaa417

Cited by 17 publications

(17 citation statements)

References 39 publications

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“…As has been shown in previous work, marR mutations are energetically costly, and the presence of a marR mutation can decrease fitness without a selective pressure (37). Indeed, marR variants detected clinically in UPEC isolates often include compensatory mutations that mitigate this growth fitness cost but consequently attenuates antimicrobial resistance (37). Likewise, we observed a significant decrease in growth rate of marR mutant strains when compared to the parent WT strain in a quetiapine-free environment.…”

Section: Discussionsupporting

confidence: 82%

“…While we did not observe a significant role for marR mutations in antimicrobial resistance, we demonstrated that these mutations were beneficial for growth in the environment in which quetiapine is present. As has been shown in previous work, marR mutations are energetically costly, and the presence of a marR mutation can decrease fitness without a selective pressure (37). Indeed, marR variants detected clinically in UPEC isolates often include compensatory mutations that mitigate this growth fitness cost but consequently attenuates antimicrobial resistance (37).…”

Section: Discussionmentioning

confidence: 82%

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The Atypical Antipsychotic Quetiapine Induces Multiple Antibiotic Resistance in Escherichia coli

Kyono

Ellezian

et al. 2021

Preprint

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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 six weeks. Quetiapine-exposed isolates exhibited an increase in minimal inhibitory concentrations (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 RT-qPCR analysis showed increased levels of marA, acrA, and tolC mRNAs and a reduced level 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 re-evaluated their resistant phenotypes using MIC and RT-qPCR assays. While marR mutations induced a robust activity of the mar operon, they resulted in only a modest increase 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.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 82%

The Atypical Antipsychotic Quetiapine Induces Multiple Antibiotic Resistance in Escherichia coli

Kyono

Ellezian

et al. 2021

Preprint

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“…Inactivation mutations of MarA have recently been shown to be selected to reduce the fitness cost imposed by mutations in marR , which cause overexpression of marA . 33 Therefore, the selection of marA mutations in this study is most likely due to the presence of a marR S65fs mutation in genetic background rather than the specific cost imposed by the Cip R rpoB mutations. Second-site mutations in RNAP genes ( rpoA, rpoB and rpoC ) were previously shown to reduce the fitness costs imposed by rpoB mutations that increase resistance to rifampicin.…”

Section: Resultsmentioning

confidence: 91%

Mutant RNA polymerase can reduce susceptibility to antibiotics via ppGpp-independent induction of a stringent-like response

Brandis

Granström

Leber

et al. 2020

Journal of Antimicrobial Chemotherapy

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Background Mutations in RNA polymerase (RNAP) can reduce susceptibility to ciprofloxacin in Escherichia coli, but the mechanism of transcriptional reprogramming responsible is unknown. Strains carrying ciprofloxacin-resistant (CipR) rpoB mutations have reduced growth fitness and their impact on clinical resistance development is unclear. Objectives To assess the potential for CipRrpoB mutations to contribute to resistance development by estimating the number of distinct alleles. To identify fitness-compensatory mutations that ameliorate the fitness costs of CipRrpoB mutations. To understand how CipRrpoB mutations reprogramme RNAP. Methods E. coli strains carrying five different CipRrpoB alleles were evolved with selection for improved fitness and characterized for acquired mutations, relative fitness and MICCip. The effects of dksA mutations and a ppGpp0 background on growth and susceptibility phenotypes associated with CipRrpoB alleles were determined. Results The number of distinct CipRrpoB mutations was estimated to be >100. Mutations in RNAP genes and in dksA can compensate for the fitness cost of CipRrpoB mutations. Deletion of dksA reduced the MICCip for strains carrying CipRrpoB alleles. A ppGpp0 phenotype had no effect on drug susceptibility. Conclusions CipRrpoB mutations induce an ppGpp-independent stringent-like response. Approximately half of the reduction in ciprofloxacin susceptibility is caused by an increased affinity of RNAP to DksA while the other half is independent of DksA. Stringent-like response activating mutations might be the most diverse class of mutations reducing susceptibility to antibiotics.

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“…For example, it is reported that the acquisition of mobile bla NDM-5positive plasmids in Enterobacteriaceae or K. pneumoniae showed little fitness cost on host bacteria (Ma et al, 2020;Huang et al, 2021). It is plausible that antibiotic resistance is determined by interactions between the resistance gene and bacterial host, not only by the existence of the resistance gene (Praski Alzrigat et al, 2021). San et al found that a small plasmid pB1000 carrying bla ROB-1 was able to improve bacterial resistance levels by increasing fitness advantages (San Millan and Maclean, 2017;Sun et al, 2019b).…”

Section: Discussionmentioning

confidence: 99%

Large-Scale Analysis of Fitness Cost of tet(X4)-Positive Plasmids in Escherichia coli

Tang

Cai

Jiang

et al. 2022

Front. Cell. Infect. Microbiol.

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Tigecycline is one of important antimicrobial agents for the treatment of infections caused by multidrug-resistant (MDR) Gram-negative bacteria. However, the emergence and prevalence of plasmid-mediated tigecycline resistance gene tet(X4) are threatening human and animal health. Fitness cost elicited by resistance plasmids is a key factor affecting the maintenance and transmission of antibiotic resistance genes (ARGs) in the host. A comparative analysis of the fitness cost of different types of tet(X4)-positive plasmids is helpful to understand and predict the prevalence of dominant plasmids. In this study, we performed a large-scale analysis of fitness cost of tet(X4)-positive plasmids origin from clinical isolates. These plasmids were successfully electroporated into a reference strain Escherichia coli TOP10, and a series of transformants carrying the tet(X) gene were obtained. The effects of tet(X4)-positive plasmids on the growth rate, plasmid stability, relative fitness, biofilm formation, and virulence in a Galleria mellonella model were evaluated. Consequently, we found that these plasmids resulted in varying degrees of fitness cost on TOP10, including delayed bacterial growth and attenuated virulence. Out of these plasmids, tet(X4)-harboring IncFII plasmids showed the lowest fitness cost on the host. Furthermore, by means of experimental evolution in the presence of commonly used drugs in clinic, the fitness cost of tet(X4)-positive plasmids was substantially alleviated, accompanied by increased plasmid stability. Collectively, our data reveal the differential fitness cost caused by different types of tet(X4)-positive plasmids and suggest that the wide use of tetracycline antibiotics may promote the evolution of plasmids.

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Resistance/fitness trade-off is a barrier to the evolution of MarR inactivation mutants in Escherichia coli

Cited by 17 publications

References 39 publications

The Atypical Antipsychotic Quetiapine Induces Multiple Antibiotic Resistance in Escherichia coli

The Atypical Antipsychotic Quetiapine Induces Multiple Antibiotic Resistance in Escherichia coli

Mutant RNA polymerase can reduce susceptibility to antibiotics via ppGpp-independent induction of a stringent-like response

Large-Scale Analysis of Fitness Cost of tet(X4)-Positive Plasmids in Escherichia coli

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