An international research team, led by scientists at Nanyang Technological University (NTU Singapore), has identified a novel approach to accelerate the healing of chronic wounds infected by antibiotic-resistant bacteria. The preclinical study, conducted in collaboration with the University of Geneva, focused on the bacterium Enterococcus faecalis, which significantly impedes wound healing.
The findings reveal that, unlike other bacteria that release toxins during infections, E. faecalis generates reactive oxygen species (ROS), which hinders the healing process of human skin cells. The study established that this bacterium utilizes a previously unidentified mechanism known as extracellular electron transport (EET) to produce ROS, thereby activating the unfolded protein response (UPR) in epithelial cells. This activation disrupts the cells’ migration, essential for healing.
The research team, including co-senior authors Guillaume Thibault, PhD, and Kimberly Kline, PhD, published their findings in the journal Science Advances. In their paper titled “Enterococcus faecalis redox metabolism activates the unfolded protein response to impair wound healing,” they concluded that EET is a virulence mechanism linking bacterial metabolism to host cell dysfunction, paving the way for new therapeutic strategies for chronic infections.
Chronic wounds pose a significant health challenge worldwide, with an estimated 18.6 million individuals developing diabetic foot ulcers each year. These wounds often lead to lower-limb amputations and are frequently complicated by persistent infections that hinder recovery. In Singapore alone, chronic wounds—including diabetic foot ulcers, pressure injuries, and venous leg ulcers—affect over 16,000 individuals annually, particularly among seniors and those with diabetes.
In the context of chronic infections, E. faecalis is an opportunistic pathogen commonly found in difficult-to-treat biofilm-associated infections. The authors noted, “Enterococcus faecalis is a gut commensal and opportunistic pathogen that causes difficult-to-treat biofilm-associated infections, including catheter-associated urinary tract infections and infective endocarditis.” Given the rising concern of antibiotic resistance, understanding the biological mechanisms that disrupt healing is crucial.
The research demonstrated that the metabolic process of EET in E. faecalis continuously produces hydrogen peroxide, a potent reactive oxygen species that can damage living tissue. Laboratory experiments indicated that oxidative stress initiates the UPR in keratinocyte skin cells, responsible for skin repair. When activated, this stress response effectively inhibits the cells from migrating to close the wound, complicating healing efforts.
The team also discovered that a genetically modified strain of E. faecalis lacking the EET pathway produced significantly less hydrogen peroxide and did not impede wound healing. This confirmed the central role of this metabolic pathway in the bacterium’s ability to disrupt skin repair mechanisms.
In a promising development, researchers tested whether neutralizing hydrogen peroxide could reverse the damage caused by E. faecalis. By applying catalase, a naturally occurring antioxidant enzyme that breaks down hydrogen peroxide, they successfully reduced cellular stress and restored the cells’ capacity to migrate and heal. This approach offers an innovative alternative to traditional antibiotics, potentially addressing antibiotic-resistant strains of E. faecalis.
The study’s authors emphasized, “These findings not only establish a role for EET in ROS generation but also, through its interaction with the host UPR, establish it as a metabolic virulence mechanism by which E. faecalis disrupts epithelial repair.” Thibault highlighted the importance of targeting the harmful products generated by bacteria rather than solely focusing on antibiotic treatments.
The implications of this research extend beyond the laboratory. The findings could lead to new treatments for patients with non-healing wounds, suggesting that wound dressings infused with antioxidants like catalase may prove effective in future therapies. As antioxidants are already well understood and widely used, this approach could expedite the transition from research to clinical application.
Moving forward, the team plans to conduct further studies to determine the most effective delivery methods for antioxidants in human clinical trials. They recommend future research to explore the role of EET in vivo and its potential regulation within polymicrobial environments, which may enhance the ability to combat E. faecalis infections resistant to traditional antibiotic therapies.
