An international team of scientists led by researchers from Nanyang Technological University, Singapore (NTU Singapore), has identified a mechanism that contributes to the healing delays in chronic wounds infected by antibiotic-resistant bacteria. Their study, conducted in collaboration with the University of Geneva, reveals how the bacterium Enterococcus faecalis actively hinders the healing process, offering potential new therapeutic strategies for affected patients.
The research, detailed in the journal Science Advances, indicates that E. faecalis does not release toxins, as many other bacteria do. Instead, it generates reactive oxygen species (ROS), which disrupt the function of human skin cells, preventing effective wound healing. The study’s findings are based on experiments conducted on mice and human cells, highlighting the unique role of extracellular electron transport (EET) in this process.
Through their investigation, the team discovered that the metabolic activity of E. faecalis leads to the continuous production of hydrogen peroxide, a potent ROS. This byproduct activates the unfolded protein response (UPR) in epithelial cells, a cellular stress response that impedes their migration and ability to repair wounds. Co-senior author Guillaume Thibault, PhD, an associate professor at NTU, emphasized the significance of these findings in establishing a link between bacterial metabolism and host cell dysfunction.
Chronic wounds represent a major health issue worldwide, with approximately 18.6 million people developing diabetic foot ulcers each year. In Singapore alone, over 16,000 cases of chronic wounds, including diabetic foot ulcers and pressure injuries, are reported annually, particularly affecting older adults and individuals with diabetes.
The research team, which includes co-senior author Kimberly Kline, PhD, from the University of Geneva, has previously demonstrated that E. faecalis infections compromise wound healing. With rising antibiotic resistance in some strains of this bacterium, understanding the underlying biological mechanisms has become increasingly critical.
The study found that by genetically modifying a strain of E. faecalis to lack the EET pathway, researchers were able to significantly reduce hydrogen peroxide production. This modification restored the wound healing process, confirming that the EET mechanism is central to the bacterium’s ability to disrupt skin repair.
To further explore potential treatments, the researchers tested whether neutralizing hydrogen peroxide could reverse the damage caused by E. faecalis. By applying catalase, a natural antioxidant enzyme that breaks down hydrogen peroxide, they observed a reduction in cellular stress and an enhancement in skin cell migration. This suggests a promising avenue for treating chronic wounds without relying solely on antibiotics.
Thibault noted, “Our findings indicate that the bacteria’s metabolism itself is the weapon, which was a surprising discovery.” Rather than focusing on eradicating the bacteria, the research suggests that neutralizing the harmful products generated by E. faecalis could restore the healing process. This approach may be particularly effective against antibiotic-resistant strains, potentially transforming the treatment landscape for chronic infections.
As the study employed human skin cells, its findings are relevant to human physiology and could lead to innovative treatments for patients with non-healing wounds. The team proposes that wound dressings infused with antioxidants like catalase could serve as effective future treatments.
Given that antioxidants are already well understood and widely used, the researchers believe this strategy could facilitate a faster transition from laboratory research to clinical application compared to developing new drugs.
Looking ahead, the team aims to conduct human clinical trials after optimizing the delivery of antioxidants through ongoing studies in animal models. They also intend to investigate the role of EET in vivo and its implications within polymicrobial environments, further paving the way for targeted therapies against E. faecalis infections that are increasingly resistant to conventional antibiotic treatments.
In summary, this research not only sheds light on the complex interactions between bacteria and human cells but also offers a potential new direction in the fight against chronic wounds and antibiotic resistance.
