An international team of scientists has revealed a new mechanism that could enhance the healing of chronic wounds infected by antibiotic-resistant bacteria. Led by researchers from Nanyang Technological University (NTU Singapore) in collaboration with the University of Geneva, the study focuses on the bacterium Enterococcus faecalis, a common pathogen that complicates wound healing.
The preclinical study, conducted on mice and human cells, discovered that E. faecalis hinders wound repair through a unique process. Unlike other bacteria that produce toxins, E. faecalis generates reactive oxygen species (ROS) that disrupt the healing of human skin cells. The team identified extracellular electron transport (EET) as a previously unrecognized mechanism responsible for ROS production, which activates the unfolded protein response (UPR) in epithelial cells. This response impedes the cells’ migration necessary for wound healing.
In their findings published in Science Advances, the researchers noted, “Our findings establish EET as a virulence mechanism that links bacterial redox metabolism to host cell stress and impaired repair, offering new avenues for therapeutic intervention in chronic infections.” The study’s co-senior authors, Guillaume Thibault, PhD, from NTU and Kimberly Kline, PhD, from the University of Geneva, emphasized the potential for this research to lead to innovative treatment strategies.
Chronic wounds present a significant health challenge globally, with an estimated 18.6 million individuals developing diabetic foot ulcers annually. In Singapore alone, over 16,000 cases of chronic wounds, including diabetic foot ulcers, are reported each year. These wounds are particularly prevalent among older adults and individuals with diabetes, often leading to severe complications such as lower-limb amputations.
The study outlines how E. faecalis, an opportunistic pathogen, is commonly involved in chronic infections. The bacterium’s ability to establish biofilms makes infections difficult to treat, especially as some strains have developed resistance to multiple antibiotics. The study highlights that the biological mechanisms by which E. faecalis disrupts healing have remained largely unclear until now.
The researchers discovered that the extracellular electron transport process in E. faecalis continuously produces hydrogen peroxide, a highly reactive ROS that can damage tissue. Laboratory experiments indicated that this oxidative stress triggers the unfolded protein response in keratinocyte skin cells, which are essential for skin repair. When activated, the UPR effectively immobilizes these cells, preventing them from migrating to close wounds.
Importantly, the team found that a genetically modified strain of E. faecalis lacking the EET pathway produced significantly less hydrogen peroxide and did not hinder wound healing. This reinforced the idea that the metabolic pathway is crucial for the bacterium’s impact on skin repair.
To further explore treatment options, the researchers tested the effects of neutralizing hydrogen peroxide on damaged skin cells. By administering catalase, a naturally occurring antioxidant enzyme that breaks down hydrogen peroxide, they were able to reduce cellular stress and restore the cells’ ability to migrate and heal. This approach could provide an alternative to traditional antibiotics, especially for antibiotic-resistant strains of E. faecalis.
The researchers concluded, “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 added, “Instead of focusing on killing the bacteria with antibiotics, we can now neutralize it by blocking the harmful products it generates and restoring wound healing.”
Given that the study utilized human skin cells, the findings have significant implications for human health. The researchers propose that wound dressings infused with antioxidants like catalase could emerge as effective treatments in the future. The established understanding of antioxidants makes this strategy more likely to transition from laboratory research to clinical application swiftly, compared to developing new drugs.
Looking ahead, the team plans to advance their research into human clinical trials after optimizing the delivery of antioxidants in ongoing animal studies. They recommend further investigation into the role of EET in vivo, its regulation in complex microbial environments, and the potential for targeting redox metabolism to address increasingly resistant E. faecalis infections.
This innovative research opens new pathways for combating chronic wounds and addressing the ongoing challenge of antibiotic resistance in healthcare.
