V-161: A breakthrough in the fight against antibiotic-resistant VRE infections
A recent study has demonstrated a promising approach for fighting antibiotic resistance by identifying a compound, V-161, that inhibits a sodium-pumping enzyme critical for VRE survival under alkaline conditions in the intestine while preserving beneficial bacteria.
This breakthrough offers hope for treating hospital infections and tackling the global threat of antibiotic-resistant bacteria.
A team of researchers led by Professor Takeshi Murata from the Graduate School of Science, Chiba University, Japan, has discovered a promising new compound, V-161, which 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, used as a safer, more tractable model for studying the enzyme. This study was published online in Nature Structural & Molecular Biology.
Dr. Murata explains, “This enzyme helps pump sodium ions out of the cell, aiding in the survival of VRE, especially in alkaline environments like the human gut. This enzyme is absent in beneficial bacteria like lactobacilli, and while humans have a similar enzyme, it serves different functions. This makes the Na+-transporting V-ATPase in VRE an ideal target for selective antimicrobial treatments.” He further states, “We screened over 70,000 compounds to identify potential inhibitors of the enzyme Na+-V-ATPase. Among these, V-161 stood out as a strong candidate, demonstrating significant effectiveness in reducing VRE growth under alkaline conditions—an environment critical for the survival of this resistant pathogen.” Following this, further studies revealed that V-161 not only inhibited the enzyme function but also reduced VRE colonization in the mouse small intestine, highlighting its therapeutic potential.
A major finding of this study was the high-resolution structural analysis of the membrane V0 domain of the enzyme, revealing detailed insights into how V-161 binds to it and disrupts the enzyme function. V-161 targets the interface between the c-ring and the a-subunit of the enzyme, effectively blocking sodium transport. This structural information is critical to understanding the workings of the compound and provides a foundation for developing drugs that target this enzyme.
