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<p>Antibiotic efflux plays a key role for the multidrug resistance in Gram-negative bacteria. Multidrug efflux pumps of the resistance nodulation and cell division (RND) superfamily function as part of cell envelope spanning systems and provide resistance to diverse antibiotics. Here, we identify two phylogenetic clusters of RND proteins with conserved binding pocket residues and show that the transfer of a single conserved residue between both clusters affects the resistance phenotype not only due to changes in the physicochemical properties of the binding pocket, but also due to an altered equilibrium between the conformational states of the transport cycle. We demonstrate, using single-particle cryo-electron microscopy, that AcrB and OqxB, which represent both clusters, adopt fundamentally different apo states, implying distinct mechanisms for initial substrate binding. The observed conformational plasticity appears phylogenetically conserved and likely plays a role in the diversification of the resistance phenotype among homologous RND pumps.</p>

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Conformational plasticity across phylogenetic clusters of RND multidrug efflux pumps and its impact on substrate specificity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月26日

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  • Mariya Lazarova,
  • Thomas Eicher,
  • Clara Börnsen,
  • Hui Zeng,
  • Mohd Athar,
  • Ui Okada,
  • Eiki Yamashita,
  • Inga M. Spannaus,
  • Max Borgosch,
  • Hi-jea Cha,
  • Attilio V. Vargiu,
  • Satoshi Murakami,
  • Kay Diederichs,
  • Achilleas S. Frangakis,
  • Klaas M. Pos

摘要

Antibiotic efflux plays a key role for the multidrug resistance in Gram-negative bacteria. Multidrug efflux pumps of the resistance nodulation and cell division (RND) superfamily function as part of cell envelope spanning systems and provide resistance to diverse antibiotics. Here, we identify two phylogenetic clusters of RND proteins with conserved binding pocket residues and show that the transfer of a single conserved residue between both clusters affects the resistance phenotype not only due to changes in the physicochemical properties of the binding pocket, but also due to an altered equilibrium between the conformational states of the transport cycle. We demonstrate, using single-particle cryo-electron microscopy, that AcrB and OqxB, which represent both clusters, adopt fundamentally different apo states, implying distinct mechanisms for initial substrate binding. The observed conformational plasticity appears phylogenetically conserved and likely plays a role in the diversification of the resistance phenotype among homologous RND pumps.