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. 2025 Mar;32(3):450-458.
doi: 10.1038/s41594-024-01419-y. Epub 2024 Nov 21.

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

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

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

Kano Suzuki et al. Nat Struct Mol Biol. 2025 Mar.

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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Conflict of interest statement

Competing interests: The authors declare no competing interests.

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