An international team of scientists has made significant strides in understanding how to accelerate the healing of chronic wounds infected by antibiotic-resistant bacteria. Led by researchers at Nanyang Technological University (NTU Singapore), the collaborative study with the University of Geneva revealed that the bacterium Enterococcus faecalis actively hinders the healing process in human skin cells.
The preclinical study demonstrated that unlike other bacteria that produce toxins during infections, E. faecalis generates reactive oxygen species (ROS). These ROS impair the healing of chronic wounds, a condition affecting millions globally. The research, published in the journal Science Advances, identifies a previously unrecognized mechanism—extracellular electron transport (EET)—which enables E. faecalis to produce ROS and activate the unfolded protein response (UPR) in epithelial cells. This activation significantly impedes cell migration necessary for wound healing.
Unveiling the Mechanism Behind Impaired Healing
The research team, co-led by Guillaume Thibault, PhD, from NTU, and Kimberly Kline, PhD, from the University of Geneva, focused on a critical link between bacterial metabolism and host cell dysfunction. Their findings indicate that E. faecalis employs EET to continuously produce hydrogen peroxide, a potent ROS that damages living tissue. Laboratory experiments revealed that this oxidative stress triggers the UPR in keratinocyte skin cells, effectively immobilizing them and preventing necessary migration to close wounds.
“Our findings establish EET as a virulence mechanism that links bacterial redox metabolism to host cell stress and impaired repair,” the researchers concluded. This insight offers a new therapeutic avenue for addressing chronic wounds, which affect an estimated 18.6 million people worldwide each year, particularly those suffering from diabetes.
In Singapore, the prevalence of chronic wounds, including diabetic foot ulcers and pressure injuries, surpasses 16,000 cases annually. These wounds are notably challenging to treat and frequently result in lower-limb amputations due to persistent infections that complicate recovery.
Targeting the Root Cause of Chronic Wounds
The study’s authors emphasize that traditional methods of combating infections, such as antibiotics, are becoming increasingly ineffective against strains of E. faecalis that exhibit resistance to multiple antibiotics. The research highlights the necessity of addressing the biological mechanisms that delay healing rather than solely focusing on eliminating the bacteria.
By genetically modifying a strain of E. faecalis to lack the EET pathway, the researchers observed a significant decrease in hydrogen peroxide production, which in turn allowed normal wound healing to resume. This finding underscores the importance of targeting the metabolic processes of the bacteria rather than attempting to kill them.
To further explore therapeutic options, the team tested the effects of catalase, an antioxidant enzyme that breaks down hydrogen peroxide, on damaged skin cells. This treatment reduced cellular stress and restored the skin cells’ ability to migrate and heal. The researchers propose that future treatments could involve wound dressings infused with antioxidants like catalase, providing a less invasive approach to managing chronic infections.
Thibault noted, “Instead of focusing on killing the bacteria, which is increasingly difficult, we can now neutralize the harmful products it generates and restore wound healing.” This approach could potentially streamline the transition from laboratory research to clinical application, as antioxidants are already well understood and widely used.
As the research progresses, the team plans to conduct further studies to determine the effectiveness of antioxidant delivery methods in animal models. The ultimate goal is to pave the way for human clinical trials that could lead to innovative treatments for patients suffering from non-healing wounds.
In their concluding remarks, the authors suggest that future investigations should examine the role of EET in vivo and its interactions within polymicrobial environments, emphasizing the potential for targeting redox metabolism to address the growing challenge of antibiotic-resistant E. faecalis infections.
