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<p>Wall teichoic acid (WTA) is a polyol phosphate polymer that covalently decorates peptidoglycan of gram-positive bacteria, including <i>Staphylococcus aureus</i>. 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 <i>S. aureus</i> TarGH in the&#xa0;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 <i>S. aureus</i> and other gram-positive bacterial infections.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月4日

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  • 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

摘要

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.