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Conformational restriction shapes the inhibition of a multidrug efflux adaptor protein

Author

Listed:
  • Benjamin Russell Lewis

    (King’s College London)

  • Muhammad R. Uddin

    (University of Oklahoma)

  • Mohammad Moniruzzaman

    (University of Oklahoma)

  • Katie M. Kuo

    (Georgia Institute of Technology)

  • Anna J. Higgins

    (University of Leeds)

  • Laila M. N. Shah

    (King’s College London)

  • Frank Sobott

    (University of Leeds)

  • Jerry M. Parks

    (Oak Ridge National Laboratory)

  • Dietmar Hammerschmid

    (King’s College London)

  • James C. Gumbart

    (Georgia Institute of Technology
    Georgia Institute of Technology)

  • Helen I. Zgurskaya

    (University of Oklahoma)

  • Eamonn Reading

    (King’s College London)

Abstract

Membrane efflux pumps play a major role in bacterial multidrug resistance. The tripartite multidrug efflux pump system from Escherichia coli, AcrAB-TolC, is a target for inhibition to lessen resistance development and restore antibiotic efficacy, with homologs in other ESKAPE pathogens. Here, we rationalize a mechanism of inhibition against the periplasmic adaptor protein, AcrA, using a combination of hydrogen/deuterium exchange mass spectrometry, cellular efflux assays, and molecular dynamics simulations. We define the structural dynamics of AcrA and find that an inhibitor can inflict long-range stabilisation across all four of its domains, whereas an interacting efflux substrate has minimal effect. Our results support a model where an inhibitor forms a molecular wedge within a cleft between the lipoyl and αβ barrel domains of AcrA, diminishing its conformational transmission of drug-evoked signals from AcrB to TolC. This work provides molecular insights into multidrug adaptor protein function which could be valuable for developing antimicrobial therapeutics.

Suggested Citation

  • Benjamin Russell Lewis & Muhammad R. Uddin & Mohammad Moniruzzaman & Katie M. Kuo & Anna J. Higgins & Laila M. N. Shah & Frank Sobott & Jerry M. Parks & Dietmar Hammerschmid & James C. Gumbart & Helen, 2023. "Conformational restriction shapes the inhibition of a multidrug efflux adaptor protein," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39615-x
    DOI: 10.1038/s41467-023-39615-x
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    References listed on IDEAS

    as
    1. Eamonn Reading & Zainab Ahdash & Chiara Fais & Vito Ricci & Xuan Wang-Kan & Elizabeth Grimsey & Jack Stone & Giuliano Malloci & Andy M. Lau & Heather Findlay & Albert Konijnenberg & Paula J. Booth & P, 2020. "Perturbed structural dynamics underlie inhibition and altered efflux of the multidrug resistance pump AcrB," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    2. Souvik Bhattacharyya & David M. Walker & Rasika M. Harshey, 2020. "Dead cells release a ‘necrosignal’ that activates antibiotic survival pathways in bacterial swarms," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    3. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
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