An international team of scientists, led by Nanyang Technological University, Singapore (NTU Singapore), has discovered a new way that could speed up the healing of chronic wounds infected by antibiotic-resistant bacteria.
Worldwide, chronic wounds represent a major health challenge, with an estimated 18.6 million people developing diabetic foot ulcers [1] each year. Up to one in three people with diabetes are at risk of developing a foot ulcer during their lifetime.
These wounds are a leading cause of lower-limb amputations and are frequently complicated by persistent infections that prevent healing.
In Singapore, chronic wounds such as diabetic foot ulcers, pressure injuries and venous leg ulcers are increasingly common, with over 16,000 cases annually, particularly among older adults and people with diabetes [2] .
Published in Science Advances, the study done with collaborators at the University of Geneva, Switzerland, shows how a common bacterium, Enterococcus faecalis (E. faecalis), actively prevents wound healing. The team also demonstrated how neutralising this biological process can allow skin cells to recover and close wounds.
E. faecalis is an opportunistic pathogen frequently found in chronic infections such as diabetic foot ulcers. These wounds are difficult to treat and often fail to heal, increasing the risk of complications and amputation.
Antibiotic resistance is also an increasing concern in E. faecalis, with some strains resistant to several commonly used antibiotics, making certain infections difficult to treat.
While such infections are known to delay healing, the biological mechanism behind this disruption has remained unclear to doctors and scientists.
The study is 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 a visiting professor at SCELSE – Singapore Centre for Environmental Life Sciences and Engineering, at NTU.
The team discovered that unlike other bacteria, which produce toxins when they infect wounds, E. faecalis produces a metabolic product called reactive oxygen species (ROS) that impairs the healing process of human skin cells.
Mechanism that disrupts wound healing
First author of the paper, NTU Research Fellow Dr Aaron Tan, found that E. faecalis uses a metabolic process known as extracellular electron transport (EET), which continuously produces hydrogen peroxide, a highly reactive oxygen species that can damage living tissue.
When present in infected wounds, this bacterium produces hydrogen peroxide, which damages human skin cells through oxidative stress.
Laboratory experiments showed that oxidative stress triggers a cellular defence mechanism known as the "unfolded protein response" in skin cells called keratinocytes, which are responsible for skin repair.
This unfolded protein response is normally used by cells to cope with damage by slowing down protein production and other vital activities, so that they can recover.
Once activated, the stress response effectively paralyses the cells, preventing them from moving to close the wound, a process known as migration.
When the researchers used a genetically modified strain of E. faecalis that lacked the EET pathway, the bacteria produced significantly less hydrogen peroxide and were unable to block wound healing.
This confirmed that the metabolic pathway was central to the bacterium's ability to disrupt skin repair. The team then tested whether neutralising the hydrogen peroxide could reverse the damage.
Potential solution that bypasses antibiotic-resistance
By treating affected skin cells with catalase, a naturally occurring antioxidant enzyme that breaks down hydrogen peroxide, the researchers reduced cellular stress and thus restored the cells' ability to migrate and heal.
This offers another solution to tackle antibiotic-resistant E. faecalis strains rather than trying to kill or inhibit them with antibiotics.
"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 neutralise it by blocking the harmful products it generates and restoring wound healing. Instead of targeting the source, we neutralise the actual cause of the chronic wounds – the reactive oxygen species."
The study establishes a direct link between bacterial metabolism and host cell dysfunction, offering a new therapeutic strategy for chronic wounds.
The researchers suggest that wound dressings infused with antioxidants such as catalase could be an effective treatment in future.
Because antioxidants like catalase are already widely used and well understood, the researchers believe this strategy could shorten the path from laboratory research to clinical application, compared with developing a new drug.
As the study used human skin cells to demonstrate the mechanism, the findings are relevant to human physiology and may pave the way for new treatments for patients with non-healing wounds.
The team aims to move towards human clinical trials after determining the most effective way to deliver antioxidants through ongoing studies in animal models.
