An international team of researchers led by NTU Singapore has identified a new approach that could accelerate the healing of chronic wounds infected with antibiotic-resistant bacteria. Chronic wounds are a significant global health burden, with millions of people developing diabetic foot ulcers each year and many individuals with diabetes facing a high lifetime risk of these conditions. Such wounds are a major cause of lower-limb amputations and are often complicated by persistent infections that hinder recovery. In Singapore, chronic wounds including diabetic foot ulcers, pressure injuries, and venous leg ulcers are becoming increasingly common, with thousands of cases reported annually, particularly among older adults and people living with diabetes.

Published in Science Advances, an international study led by researchers from NTU Singapore in collaboration with the University of Geneva uncovers a previously unknown mechanism by which Enterococcus faecalis actively disrupts wound healing and shows how targeting this process can promote recovery. Commonly found in chronic infections such as diabetic foot ulcers, E. faecalis is an opportunistic pathogen that contributes to wounds failing to heal, significantly increasing the risk of severe infection and limb amputation. The challenge is further compounded by the growing antibiotic resistance of this bacterium, with some strains resistant to multiple commonly used drugs, limiting treatment options.

NTU Research Fellow Dr. Aaron Tan, first author of the paper, discovered that E. faecalis uses a metabolic process called extracellular electron transport (EET) to continuously generate hydrogen peroxide, a reactive oxygen species that damages living tissue. In infected wounds, this hydrogen peroxide causes oxidative stress in human skin cells, triggering the unfolded protein response in keratinocytes the cells responsible for skin repair. While this response normally helps cells recover by slowing down protein production and other essential functions, its activation in this context effectively paralyzes keratinocytes, preventing them from migrating to close the wound. In laboratory experiments, a genetically modified E. faecalis strain lacking the EET pathway produced much less hydrogen peroxide and failed to block wound healing, confirming that this metabolic process is central to the bacterium’s disruptive effect. The researchers then tested whether neutralizing the hydrogen peroxide could reverse the damage, highlighting a potential new strategy for restoring skin repair in chronic infections.

Treating affected skin cells with catalase, a natural antioxidant enzyme that breaks down hydrogen peroxide, reduced cellular stress and restored their ability to migrate and heal, offering an alternative approach to combat antibiotic-resistant E. faecalis without relying on antibiotics.  Our findings show that the bacteria’s metabolism itself is the weapon, said Assoc Prof Thibault, highlighting that neutralizing harmful metabolic byproducts rather than killing the bacteria could restore wound healing and reduce antibiotic resistance. The study links bacterial metabolism directly to host cell dysfunction and suggests that antioxidant-infused wound dressings, such as those containing catalase, could become an effective future treatment for chronic infected wounds.

Source: https://www.ntu.edu.sg/news/detail/new-way-to-disarm-antibiotic-resistant-bacteria-and-restore-healing-in-chronic-wounds