2. Academic Validation
  3. Na+-V-ATPase inhibitor curbs VRE growth and unveils Na+ pathway structure

Na+-V-ATPase inhibitor curbs VRE growth and unveils Na+ pathway structure

  • Nat Struct Mol Biol. 2024 Nov 21. doi: 10.1038/s41594-024-01419-y.
Kano Suzuki # 1 2 3,  Yoshiyuki Goto # 3 4 5 6 7,  Akihiro Otomo 8 9,  Kouki Shimizu 1,  Shohei Abe 1,  Katsuhiko Moriyama 1 2 3,  Satoshi Yasuda 1 2 3,  Yusuke Hashimoto 10,  Jun Kurushima 11,  Sho Mikuriya 1,  Fabiana L Imai 1,  Naruhiko Adachi 12 13,  Masato Kawasaki 12,  Yumi Sato 14,  Satoshi Ogasawara 1 2 3,  So Iwata 14,  Toshiya Senda 12 15 16,  Mitsunori Ikeguchi 17,  Haruyoshi Tomita 10 11,  Ryota Iino 8 9,  Toshio Moriya 12,  Takeshi Murata 18 19 20 21
Affiliations

Affiliations

  • 1 Department of Chemistry, Graduate School of Science, Chiba University, Chiba, Japan.
  • 2 Department of Quantum Life Science, Graduate School of Science, Chiba University, Chiba, Japan.
  • 3 Membrane Protein Research Center, Chiba University, Chiba, Japan.
  • 4 Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba, Japan.
  • 5 Division of Pandemic and Post-disaster Infectious Diseases, Research Institute of Disaster Medicine, Chiba University, Chiba, Japan.
  • 6 Division of Infectious Disease Vaccine R&D, Research Institute of Disaster Medicine, Chiba University, Chiba, Japan.
  • 7 Synergy Institute for Futuristic Mucosal Vaccine Research and Development (cSIMVa), Chiba University, Chiba, Japan.
  • 8 Institute for Molecular Science, National Institutes of Natural Sciences, Okazaki, Japan.
  • 9 The Graduate Institute for Advanced Studies, SOKENDAI, Shonan Village, Hayama, Japan.
  • 10 Department of Bacteriology, Graduate School of Medicine, Gunma University, Maebashi, Japan.
  • 11 Laboratory of Bacterial Drug Resistance, Graduate School of Medicine, Gunma University, Maebashi, Japan.
  • 12 Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Japan.
  • 13 Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan.
  • 14 Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 15 School of High Energy Accelerator Science, SOKENDAI, Tsukuba, Japan.
  • 16 Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Japan.
  • 17 Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan.
  • 18 Department of Chemistry, Graduate School of Science, Chiba University, Chiba, Japan. t.murata@faculty.chiba-u.jp.
  • 19 Department of Quantum Life Science, Graduate School of Science, Chiba University, Chiba, Japan. t.murata@faculty.chiba-u.jp.
  • 20 Membrane Protein Research Center, Chiba University, Chiba, Japan. t.murata@faculty.chiba-u.jp.
  • 21 Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan. t.murata@faculty.chiba-u.jp.
  • # Contributed equally.
PMID: 39572733 DOI: 10.1038/s41594-024-01419-y
Abstract

Vancomycin-resistant Enterococcus faecium (VRE) is a major cause of nosocomial infections, particularly endocarditis and sepsis. With the diminishing effectiveness of Antibiotics against VRE, new antimicrobial agents are urgently needed. Our previous research demonstrated the crucial role of Na+-transporting V-ATPase in Enterococcus hirae for growth under alkaline conditions. In this study, we identified a compound, V-161, from 70,600 compounds, which markedly inhibits E. hirae V-ATPase activity. V-161 not only inhibits VRE growth in alkaline conditions but also significantly suppresses VRE colonization in the mouse small intestine. Furthermore, we unveiled the high-resolution structure of the membrane VO part due to V-161 binding. V-161 binds to the interface of the c-ring and a-subunit, constituting the Na+ transport pathway in the membrane, thereby halting its rotation. This structural insight presents potential avenues for developing therapeutic agents for VRE treatment and elucidates the Na+ transport pathway and mechanism.

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