Investigators Pinpoint VRE’s Achilles Heel

December 12, 2019

Vancomycin-resistant enterococci (VRE) not only wards off antibiotics and what the body’s immune system throws at it, but it becomes even more lethal in doing so.

Vancomycin-resistant enterococci (VRE) not only wards off antibiotics and what the body’s immune system throws at it, but it becomes even more lethal in doing so, investigators at the University of Texas Health Science Center at Houston (UTHealth) noted in a recent study.

The research team sought to find out why and concluded that VRE, one of the more virulent healthcare-acquired and multidrug-resistant infections, contains a protein called LiaX which shields the bacteria. Their findings were published recently in the Proceedings of the National Academy of Sciences of the United States of America.

Senior author Cesar Arias, MD, a professor at McGovern Medical School at UTHealth, said in a press release that LiaX acts as the “main mediator of the response against antibiotics and the first line of defense of our immune system…” He adds this study’s findings “will open major therapeutic and diagnostic research avenues against these organisms which are associated with disease in critically ill patients.”

He tells Infection Control Today that “we think that targeting this protein and the system could disarm VRE and control infections, GI colonization and patient-to-patient transmission.”

Enterococci live naturally in the gut and the bacteria are not usually an issue for healthy people but can become a problem for someone with a compromised immune system-many of whom can be found in hospitals. “However, the discovery of this defense mechanism to both antibiotic treatment and the immune response the body naturally produces points to the overall evolution of germs to continue to grow increasingly drug-resistant and resilient,” according to investigators.

One of the major findings in the study is that LiaX not only protects VRE but that protection inherently makes the bacteria more lethal during infection. 

VRE infects 54,500 hospitalized patients a year, and about 5400 die from it, according to the US Centers for Disease Control and Prevention. The frontline therapy for severe multidrug-resistant enterococcal infections, daptomycin, targets the bacterial cell membrane. 

“What we revealed is that not only is LiaX acting as a sentinel protein that latches on to daptomycin, but it can sense the antimicrobial peptides created by our immune systems and elicit the same cell restructuring response,” said Ayesha Khan, at UTHealth Graduate School of Biomedical Sciences and the study’s main author.

Khan calls LiaX “the master modulator of resistance, and it basically tells the bacteria to remodel their protective cell envelope, causing daptomycin to bind away from the septum and allowing the cell to survive.” 

Kahn tells Infection Control Today that VRE can “sense” antimicrobials, a key step to antibiotic resistance. “We are working to see if we can block this protein or develop molecules to incapacitate the entire cell envelope stress response system, which wouldn't kill the bacteria on its own, but it would hinder their ability to evolve. We are transforming the way we think about antibiotics.”

That said, Kahn adds that antibiotic resistance will always be a problem. “No matter how many new antibiotics we develop, bacteria will figure out a way to defend themselves.”

Kahn said that in nosocomial settings, strains like VRE might be evolving in the presence of disinfectants that are used to clean patient rooms. “As we know, VRE are easily spread through contaminated surfaces in the hospital, patient-to-patient room transfers, contaminated equipment and of course person-to-person spread which most commonly is through contaminated hands.”

VREs evolve constantly as commensals when they are exposed to stress like bile salts in the gut or they evolve when exposed to chlorhexidine, which is used to bath patients. If they do infect an immunocompromised patient, they can become resistant to antibiotics used for therapy and the patient will have a harder time using the immune system to clear the infection.

“Hand hygiene is extremely important to ensure there is no patient-to-patient, patient-to-staff, and staff-to-staff spread of these VRE strains,” said Kahn. “Clearly there are a lot of drug-resistant clones out there, and the study shows how capable and clever they can be at adapting. The last thing we need is to be passing them around the hospital because hand hygiene isn’t strictly enforced.”