The rise of antibiotic-resistant bacteria is a global health concern, with studies predicting over ten million deaths per year by 2050 from these resistant infections. The World Health Organization (WHO) has identified twelve critical antibiotic-resistant pathogens, including vancomycin-resistant Enterococcus (VRE), such as Enterococcus faecium (E. faecium). VRE causes serious hospital-acquired infections such as endocarditis and sepsis and has developed resistance to multiple antibiotics, highlighting the urgent need for new antimicrobial treatments. V-161, a novel compound that targets the sodium-V-ATPase enzyme in this bacterium, significantly reduces its growth and colonization. The researchers’ investigation demonstrated a promising approach to combat antibiotic resistance by identifying this compound, which inhibits an enzyme critical to the survival of VRE.
This discovery offers hope for the treatment of hospital-acquired infections and to counter the global threat of antibiotic-resistant bacteria. In response to this crisis, a team of researchers led by Professor Takeshi Murata of the Graduate School of Science, Chiba University, Japan, has discovered a promising new compound, V-161, that effectively inhibits the growth of VRE. Their research examined a sodium-pumping enzyme found in these bacteria called Na+-transporting V-ATPase found in E. hirae, a close relative of E. faecium, which was used as a safer and more tractable model to study the enzyme. This study, published online in Nature Structural & Molecular Biology last November 21, 2024, hypothesized that Na+-transporting V-ATPase could play a key role in the development of an antibiotic that specifically targets VRE without affecting beneficial bacteria.
This enzyme helps pump sodium ions out of the cell, which helps VRE survive, especially in alkaline environments like the human gut. This enzyme is absent from beneficial bacteria such as lactobacilli, and although humans have a similar enzyme, it has different functions. This makes the sodium-transporting V-ATPase in VRE an ideal target for selective antimicrobial treatments. Further studies later revealed that V-161 not only inhibited enzyme function, but also reduced VRE colonization in the mouse small intestine. A major breakthrough from this study was the high-resolution structural analysis of the enzyme’s V0 membrane domain, which revealed detailed information about how V-161 binds to it and disrupts enzyme function. V-161 targets the interface between the C-ring and the α-subunit of the enzyme, effectively blocking sodium transport.
This structural information is critical to understanding how the compound works and provides a basis for developing drugs that target this enzyme. As part of ongoing efforts to refine V-161, the research team plans to test it against other bacterial strains to further evaluate its potential. The ultimate goal is to develop a new class of antibiotics that not only complements existing treatments but can also serve as a powerful solution to combat the growing threat of antibiotic resistance.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry
Scientific references
Suzuki KÂ et al. Nature Struct Mol Biol. 2024 Nov 21; in press.
Wei M et al. Front Cell Infect Microbiol. 2023 Sep; 13:1266674.
