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Activating alternative transport modes in a multidrug resistance efflux pump to confer chemical susceptibility

Author

Listed:
  • Peyton J. Spreacker

    (University of Wisconsin-Madison)

  • Nathan E. Thomas

    (University of Wisconsin-Madison
    University of California-San Diego)

  • Will F. Beeninga

    (University of Wisconsin-Madison)

  • Merissa Brousseau

    (University of Wisconsin-Madison)

  • Colin J. Porter

    (University of Wisconsin-Madison)

  • Kylie M. Hibbs

    (University of Wisconsin-Madison)

  • Katherine A. Henzler-Wildman

    (University of Wisconsin-Madison
    University of Wisconsin-Madison)

Abstract

Small multidrug resistance (SMR) transporters contribute to antibiotic resistance through proton-coupled efflux of toxic compounds. Previous biophysical studies of the E. coli SMR transporter EmrE suggest that it should also be able to perform proton/toxin symport or uniport, leading to toxin susceptibility rather than resistance in vivo. Here we show EmrE does confer susceptibility to several previously uncharacterized small-molecule substrates in E. coli, including harmane. In vitro electrophysiology assays demonstrate that harmane binding triggers uncoupled proton flux through EmrE. Assays in E. coli are consistent with EmrE-mediated dissipation of the transmembrane pH gradient as the mechanism underlying the in vivo phenotype of harmane susceptibility. Furthermore, checkerboard assays show this alternative EmrE transport mode can synergize with some existing antibiotics, such as kanamycin. These results demonstrate that it is possible to not just inhibit multidrug efflux, but to activate alternative transport modes detrimental to bacteria, suggesting a strategy to address antibiotic resistance.

Suggested Citation

  • Peyton J. Spreacker & Nathan E. Thomas & Will F. Beeninga & Merissa Brousseau & Colin J. Porter & Kylie M. Hibbs & Katherine A. Henzler-Wildman, 2022. "Activating alternative transport modes in a multidrug resistance efflux pump to confer chemical susceptibility," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35410-2
    DOI: 10.1038/s41467-022-35410-2
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    References listed on IDEAS

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    1. Alexander A. Shcherbakov & Grant Hisao & Venkata S. Mandala & Nathan E. Thomas & Mohammad Soltani & E. A. Salter & James H. Davis & Katherine A. Henzler-Wildman & Mei Hong, 2021. "Structure and dynamics of the drug-bound bacterial transporter EmrE in lipid bilayers," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
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    1. Alexander A. Shcherbakov & Peyton J. Spreacker & Aurelio J. Dregni & Katherine A. Henzler-Wildman & Mei Hong, 2022. "High-pH structure of EmrE reveals the mechanism of proton-coupled substrate transport," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
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