Functional Characterization of a Novel SMR-Type Efflux Pump RanQ, Mediating Quaternary Ammonium Compound Resistance in Riemerella anatipestifer

Quan, Heng; Gong, Xiaowei; Chen, Qiwei; Zheng, Fuying; Yu, Yongfeng; Liu, Donghui; Wang, Wenhui; Chu, Yuefeng

doi:10.3390/microorganisms11040907

Cited by 3 publications

(2 citation statements)

References 38 publications

(48 reference statements)

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“…The Small Multidrug Resistance (SMR) transporters are a family of efflux pumps that have been identified in many high priority pathogens, but their contributions to antibiotic resistance are minimally understood (4)(5)(6)(7)(8)(9)(10)(11). The SMR family of transporters may be broadly divided into four subfamilies, with the QAC subfamily representing the most promiscuous transporters, named for their ability to confer resistance to quaternary ammonium compounds (11).…”

Section: Introductionmentioning

confidence: 99%

“…One such mechanism is secondary active transport of toxic compounds by efflux pumps. The Small Multidrug Resistance (SMR) transporters are a family of efflux pumps that have been identified in many high priority pathogens, but their contributions to antibiotic resistance are minimally understood (3)(4)(5)(6)(7)(8)(9)(10). The SMR family may be broadly divided into four subfamilies, with the QAC subfamily representing the most promiscuous transporters (10).…”

Section: Introductionmentioning

confidence: 99%

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A Small Multidrug Resistance Transporter inPseudomonas aeruginosaConfers Substrate-Specific Resistance or Susceptibility

Wegrzynowicz,

Heelan,

Demas

et al. 2023

Preprint

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Small Multidrug Resistance (SMR) transporters are key players in bacterial defense against toxins, providing resistance to antibiotics, antiseptics, and other homeostasis-perturbing compounds in multidrug-resistant pathogens. However, recent evidence demonstrates that EmrE, an SMR fromEscherichia coliand a model for understanding transport, can also induce susceptibility to some compounds by drug-gated uncontrolled proton leak. Proton Motive Force (PMF) rundown is a relatively unexplored drug target, and is orthogonal to the targets of most known antibiotics. This requires an SMR to be merely present, rather than be the primary resistance mechanism, and dissipates the energy source for many other efflux pumps. PAsmr, an EmrE homolog fromP. aeruginosa, confers resistance to some EmrE substrates in cells and in purified systems. We hypothesized that PAsmr, like EmrE, could confer susceptibility to some compounds. Growth assays ofE. coliexpressing PAsmr displayed substrate-dependent resistance and susceptibility phenotypes, andin vitrosolid-supported membrane electrophysiology experiments revealed that PAsmr performs both antiport and substrate-gated proton uniport, confirming functional homology between PAsmr and EmrE. Growth assays ofP. aeruginosastrain PA14 demonstrated that PAsmr contributes resistance to some antimicrobial compounds, consistent with prior data, but conferssusceptibilityto at least one aminoglycoside antibiotic. Phenotypic differences betweenP. aeruginosaandE. coliexpressing PAsmr point to differential impacts of proton leak, constituting an advance in our understanding of underlying resistance mechanisms inP. aeruginosaand prompting further investigation into the role that SMRs play in antibiotic resistance in pathogens.IMPORTANCESmall multidrug resistance transporters are a class of efflux pumps found in many pathogens, but whose contributions to antibiotic resistance are poorly understood. We hypothesize that in addition to conferring resistance to toxic compounds, these transporters may also confer susceptibility by dissipating the proton-motive force. This means that an SMR merely needs to be present in the pathogen in order to be targeted (as opposed to being the primary resistance mechanism). Here, we test this hypothesis with an SMR found in the pathogenPseudomonas aeruginosaand find that it can confer both resistance and susceptibility depending upon the compounds it interacts with.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Small Multidrug Resistance Transporter inPseudomonas aeruginosaConfers Substrate-Specific Resistance or Susceptibility

Wegrzynowicz,

Heelan,

Demas

et al. 2023

Preprint

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Lysine and valine weaken antibiotic resistance in Salmonella Typhimurium induced by disinfectant stress

Wu,

Ji,

Sheng

et al. 2024

Journal of Hazardous Materials

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Substrate dependence of transport coupling and phenotype of a small multidrug resistance transporter in Pseudomonas aeruginosa

Wegrzynowicz,

Heelan,

Demas

et al. 2024

J Bacteriol

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Small multidrug resistance (SMR) transporters are key players in the defense of multidrug-resistant pathogens to toxins and other homeostasis-perturbing compounds. However, recent evidence demonstrates that EmrE, an SMR from Escherichia coli and a model for understanding transport, can also induce susceptibility to some compounds by drug-gated proton leak. This runs down the ∆pH component of the proton-motive force (PMF), reducing the viability of the affected bacteria. Proton leak may provide an unexplored drug target distinct from the targets of most known antibiotics. Activating proton leak requires an SMR to be merely present, rather than be the primary resistance mechanism, and dissipates the energy source for many other efflux pumps. PAsmr, an EmrE homolog from Pseudomonas aeruginosa , transports many EmrE substrates in cells and purified systems. We hypothesized that PAsmr, like EmrE, may confer susceptibility to some compounds via drug-gated proton leak. Growth assays of E. coli expressing PAsmr displayed substrate-dependent resistance and susceptibility phenotypes, and in vitro solid-supported membrane electrophysiology experiments revealed that PAsmr performs both antiport and substrate-gated proton uniport, demonstrating the same functional promiscuity observed in EmrE. Growth assays of P. aeruginosa strain PA14 demonstrated that PAsmr contributes resistance to some antimicrobial compounds, but no growth defect is observed with susceptibility substrates, suggesting P. aeruginosa can compensate for the proton leak occurring through PAsmr. These phenotypic differences between P. aeruginosa and E. coli advance our understanding of the underlying resistance mechanisms in P. aeruginosa and prompt further investigation into the role that SMRs play in antibiotic resistance in pathogens. IMPORTANCE Small multidrug resistance (SMR) transporters are a class of efflux pumps found in many pathogens, although their contributions to antibiotic resistance are not fully understood. We hypothesize that these transporters may confer not only resistance but also susceptibility, by dissipating the proton-motive force. This means to use an SMR transporter as a target; it merely needs to be present (as opposed to being the primary resistance mechanism). Here, we test this hypothesis with an SMR transporter found in Pseudomonas aeruginosa and find that it can perform both antiport (conferring resistance) and substrate-gated proton leak. Proton leak is detrimental to growth in Escherichia coli but not P. aeruginosa , suggesting that P. aeruginosa responds differently to or can altogether prevent ∆pH dissipation.

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Functional Characterization of a Novel SMR-Type Efflux Pump RanQ, Mediating Quaternary Ammonium Compound Resistance in Riemerella anatipestifer

Cited by 3 publications

References 38 publications

A Small Multidrug Resistance Transporter inPseudomonas aeruginosaConfers Substrate-Specific Resistance or Susceptibility

A Small Multidrug Resistance Transporter inPseudomonas aeruginosaConfers Substrate-Specific Resistance or Susceptibility

Lysine and valine weaken antibiotic resistance in Salmonella Typhimurium induced by disinfectant stress

Substrate dependence of transport coupling and phenotype of a small multidrug resistance transporter in Pseudomonas aeruginosa

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