The World Health Organization (WHO) has identified twelve critical antibiotic-resistant pathogens, including vancomycin-resistant Enterococci (VRE) infections, such as Enterococcus faecium (E. faecium).
VRE infections cause severe hospital-acquired infections like endocarditis and sepsis and have developed resistance to multiple antibiotics, highlighting the urgent need for new antimicrobial treatments.
In response to this crisis, 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 infections.
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.
The growing risk of VRE infections
VRE infections are dangerous because they are resistant to vancomycin, the drug often used to treat infections caused by enterococci.
In 2017, VRE caused an estimated 54,500 infections among hospitalised patients and 5,400 estimated deaths in the United States.
It is spread by:
- Direct person-to-person. This can be from patient to patient or from staff who have been nursing a patient who is infected or colonised with VRE and have not washed their hands appropriately between patients and/or have not worn appropriate personal protective equipment, e.g. gloves and aprons.
- Touching room surfaces or medical equipment which is contaminated and not cleaned appropriately.
- VRE that lives harmlessly in a person’s bowel (gut) can move to another area of their body, e.g. into a wound.
How the enzyme targets VRE in the body
The study hypothesised that Na+-transporting V-ATPase could play a key role in developing an antibiotic that specifically targets VRE infections without affecting beneficial bacteria.
Dr Murata explained: “This enzyme helps pump sodium ions out of the cell, aiding in the survival of VRE, especially in alkaline environments like the human gut.
“The 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 added: “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 colonisation in the mouse small intestine, highlighting its therapeutic potential.
Supporting future antibiotic development
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.
While the results are promising, the study also notes that further research is needed to make V-161 even more effective and improve its efficacy against a broader range of bacterial strains.
Despite these challenges, the findings mark a significant advancement in developing new therapeutic agents to combat VRE infections 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.
“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,” Dr Murata concluded.
The ultimate goal is to develop a new class of antibiotics that not only complements existing treatments but may also serve as a powerful solution to combat the escalating threat of antibiotic resistance.
