Novel Compound Demonstrates Activity Against Vancomycin-Resistant Enterococci
An investigational inhibitor, V-161, has been shown to reduce bacterial growth and colonization in an enzyme that is key to enterococcus proliferation.
Professor Takeshi Murata, Graduate School of Science, Chiba University
Image credit: Chiba University
Vancomycin-resistant enterococcus (VRE) is an opportunistic pathogen thatcan causes severe hospital-acquired bacterial infections like endocarditis and sepsis and has developed resistance to multiple antibiotics.1 Inpatients at risk for VRE infections include those who are immunocompromised; those who have taken vancomycin and other antibiotics over an extended period of time; patients who have had surgery; and patients who have medical devices including those with catheters.2
According to the Centers for Disease Control and Prevention (CDC), VRE caused an estimated 54,500 infections among hospitalized patients and 5,400 estimated deaths in the US in 2017.2 The World Health Organization (WHO) has identified twelve critical antibiotic-resistant pathogens, including VRE,such as enterococcus faecium(E faecium).1
New research from Japan shows an investigational compound, V-161, which targets the Na+-V-ATPase enzyme in VRE, significantly reduces bacterial growth and colonization. A recent study published in Nature Structural & Molecular Biology demonstrated V-161 inhibits a sodium-pumping enzyme critical for VRE survival under alkaline conditions in the intestine while preserving beneficial bacteria.1
Professor Takeshi Murata, Graduate School of Science, Chiba University, Japan discovered the compound and his research examined Na+-V-ATPase, a sodium-pumping enzyme found E hirae, a close relative of E faecium used as a safer, more tractable model for studying the enzyme.1
Figure 1.
Illustration credit: Chiba University
“This enzyme helps pump sodium ions out of the cell, aiding in the survival of VRE, especially in alkaline environments like the human gut,” Murata said in a statement. “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.”1
“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.”
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 (Figure 1).1
Additional animal studies showed that V-161 not only inhibited the enzyme function but also reduced VRE colonization in the mouse small intestine, highlighting its therapeutic potential.1
These findings mark a significant advancement in developing new therapeutic agents to combat VRE and other antibiotic-resistant bacteria. As part of ongoing efforts to refine V-161, the research team plans to test it against other bacterial strains to further assess its potential.1
“We hope that these efforts will ultimately yield more effective treatments for infections caused by VRE and other drug-resistant bacteria, making a significant impact on the fields of infectious diseases and public health,” Murata stated.1
