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. Online ahead of print.

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.