An international research team led by Nanyang Technological University, Singapore (NTU Singapore), has identified a promising way to help chronic wounds heal faster, including wounds infected with antibiotic resistant bacteria.
Chronic wounds are a growing global health problem. Each year, about 18.6 million people worldwide develop diabetic foot ulcers.[1] Over a lifetime, as many as one in three people with diabetes may experience a foot ulcer.
These long lasting wounds are a leading cause of lower limb amputations. Ongoing infections often make healing even harder, trapping patients in a cycle of repeated complications.
In Singapore, chronic wounds such as diabetic foot ulcers, pressure injuries and venous leg ulcers are becoming more common. More than 16,000 cases are reported each year, particularly among older adults and people living with diabetes.[2]
How a Common Bacterium Blocks Healing
The findings were published in Science Advances in collaboration with researchers from the University of Geneva, Switzerland. The study reveals how a widespread bacterium, Enterococcus faecalis (E. faecalis), can actively interfere with the body’s ability to heal wounds. The team also showed that blocking this process allows skin cells to recover and close wounds.
E. faecalis is an opportunistic pathogen often found in chronic infections such as diabetic foot ulcers. These wounds are notoriously difficult to treat and frequently fail to heal, raising the risk of serious complications and amputation.
Antibiotic resistance adds another layer of difficulty. Some strains of E. faecalis no longer respond to several commonly used antibiotics, making infections increasingly challenging to control.
While doctors have long known that infections can slow wound healing, the exact biological reason for this effect has remained unclear.
The study was jointly led by NTU Associate Professor Guillaume Thibault from the School of Biological Sciences and Professor Kimberly Kline from the University of Geneva, who is also a visiting professor at SCELSE — Singapore Centre for Environmental Life Sciences and Engineering, at NTU.
The Role of Bacterial Metabolism and Cell Stress
The researchers found that E. faecalis behaves differently from many other bacteria that infect wounds. Instead of relying mainly on toxins, it releases reactive oxygen species (ROS), a metabolic byproduct that disrupts the normal healing function of human skin cells.
First author NTU Research Fellow Dr Aaron Tan discovered that E. faecalis uses a metabolic process called extracellular electron transport (EET). This process continuously produces hydrogen peroxide, a highly reactive oxygen species capable of damaging living tissue.
When E. faecalis is present in a wound, the hydrogen peroxide it produces causes oxidative stress in nearby human skin cells.
Laboratory experiments showed that this oxidative stress activates a protective response in keratinocytes, the skin cells responsible for repairing wounds. This response is known as the “unfolded protein response.”
Under normal conditions, the unfolded protein response helps cells survive damage by slowing protein production and other essential activities, giving them time to recover.
However, once triggered in this context, the response effectively paralyzes the cells. It prevents them from moving into the wound area to seal the damaged tissue, a process known as migration.
To confirm the importance of this pathway, the researchers tested a genetically modified strain of E. faecalis that lacked the EET pathway. These altered bacteria produced much less hydrogen peroxide and were no longer able to block wound healing.
This result confirmed that the metabolic pathway plays a central role in how E. faecalis disrupts skin repair. The team then investigated whether neutralizing hydrogen peroxide could reverse the damage.
A Potential Treatment Beyond Antibiotics
When the researchers treated stressed skin cells with catalase, a naturally occurring antioxidant enzyme that breaks down hydrogen peroxide, cellular stress levels dropped. As a result, the cells regained their ability to migrate and heal the wound.
This approach offers an alternative way to address infections caused by antibiotic resistant E. faecalis. Instead of trying to kill the bacteria with antibiotics, the strategy focuses on neutralizing the harmful substances the bacteria produce.
“Our findings show that the bacteria’s metabolism itself is the weapon, which was a surprise finding previously unknown to scientists,” said Assoc Prof Thibault, who is also the Assistant Dean (International Engagement) at the College of Science.
“Instead of focusing on killing the bacteria with antibiotics, which is becoming increasingly difficult and leads to future antibiotic resistance, we can now neutralize it by blocking the harmful products it generates and restoring wound healing. Instead of targeting the source, we neutralize the actual cause of the chronic wounds — the reactive oxygen species.”
The study directly links bacterial metabolism to dysfunction in human cells, pointing to a new therapeutic strategy for chronic wounds.
The researchers suggest that future wound dressings infused with antioxidants such as catalase could help promote healing.
Because antioxidants like catalase are already widely used and well understood, the team believes this approach could move from laboratory research to clinical use faster than developing an entirely new drug.
Since the mechanism was demonstrated using human skin cells, the findings are directly relevant to human physiology and may lead to new treatments for people with non healing wounds.
Next, the researchers plan to move toward human clinical trials after identifying the most effective way to deliver antioxidants through ongoing studies in animal models.
- Armstrong, D. G. (2023). Diabetic Foot Ulcers: A Review. PubMed. Retrieved from https://pubmed.ncbi.nlm.nih.gov/37395769/
- Goh, O. Q., et al. (2023). Chronic wounds in a multiethnic Asian population: a cost of illness study [Abstract]. BMJ Open. Retrieved from https://pmc.ncbi.nlm.nih.gov/articles/PMC10510887/
