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Cryo-EM analyses unveil details of mechanism and targocil-II mediated inhibition of S. aureus WTA transporter TarGH

Author

Listed:
  • Franco K. K. Li

    (University of British Columbia)

  • Shaun C. Peters

    (University of British Columbia)

  • Liam J. Worrall

    (University of British Columbia
    University of British Columbia)

  • Tianjun Sun

    (University of British Columbia)

  • Jinhong Hu

    (University of British Columbia)

  • Marija Vuckovic

    (University of British Columbia)

  • Maya Farha

    (McMaster University)

  • Armando Palacios

    (University of British Columbia)

  • Nathanael A. Caveney

    (University of British Columbia
    University of British Columbia)

  • Eric D. Brown

    (McMaster University)

  • Natalie C. J. Strynadka

    (University of British Columbia
    University of British Columbia)

Abstract

Wall teichoic acid (WTA) is a polyol phosphate polymer that covalently decorates peptidoglycan of gram-positive bacteria, including Staphylococcus aureus. Central to WTA biosynthesis is flipping of lipid-linked precursors across the cell membrane by TarGH, a type V ABC transporter. Here, we present cryo-EM structures of S. aureus TarGH in the presence of targocil-II, a promising small-molecule lead with β-lactam antibiotic synergistic action. Targocil-II binds to the extracellular dimerisation interface of TarG, we suggest mimicking flipped but not yet released substrate. In absence of targocil-II and in complex with ATP analogue ATPγS, determined at 2.3 Å resolution, the ATPase active site is allosterically inhibited. This is due to a so far undescribed D-loop conformation, potentially minimizing spurious ATP hydrolysis in the absence of substrate. Targocil-II binding comparatively causes local and remote conformational changes through to the TarH active site, with the D-loop now optimal for ATP hydrolysis. These structures suggest an ability to modulate ATP hydrolysis in a WTA substrate dependent manner and a jammed ATPase cycle as the basis of the observed inhibition by targocil-II. The molecular insights provide an unprecedented basis for development of TarGH targeted therapeutics for treatment of multidrug-resistant S. aureus and other gram-positive bacterial infections.

Suggested Citation

  • Franco K. K. Li & Shaun C. Peters & Liam J. Worrall & Tianjun Sun & Jinhong Hu & Marija Vuckovic & Maya Farha & Armando Palacios & Nathanael A. Caveney & Eric D. Brown & Natalie C. J. Strynadka, 2025. "Cryo-EM analyses unveil details of mechanism and targocil-II mediated inhibition of S. aureus WTA transporter TarGH," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58202-w
    DOI: 10.1038/s41467-025-58202-w
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    References listed on IDEAS

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