A groundbreaking discovery has emerged that could revolutionize the treatment of chronic wounds often infected by superbugs resistant to antibiotics. An international research team spearheaded by NTU Singapore has unveiled a novel approach aimed at accelerating the healing process for these challenging conditions.
Chronic wounds pose a significant global health issue, with approximately 18.6 million individuals developing diabetic foot ulcers annually. Alarmingly, up to one-third of diabetes patients may face the risk of experiencing a foot ulcer at some point in their lives. These types of wounds are primary contributors to lower-limb amputations and are frequently exacerbated by stubborn infections that hinder healing.
In Singapore alone, the prevalence of chronic wounds, including diabetic foot ulcers, pressure sores, and venous leg ulcers, is on the rise, with over 16,000 cases reported each year—particularly affecting older adults and those living with diabetes.
Recently published in the journal Science Advances, this study, conducted in collaboration with researchers from the University of Geneva in Switzerland, reveals how a common bacterium known as Enterococcus faecalis (E. faecalis) plays a detrimental role in the healing of wounds. The research team demonstrated that by neutralizing the harmful effects of this bacterium, it is possible to enable skin cells to recover and effectively close wounds.
E. faecalis is recognized as an opportunistic pathogen that often complicates chronic infections like diabetic foot ulcers. Treating these infections is notoriously difficult, leading to a higher likelihood of complications and even amputations. Adding to the challenge is the rising issue of antibiotic resistance, with certain strains of E. faecalis defying treatment by becoming resistant to multiple commonly prescribed antibiotics.
Despite the known impact these infections have on delaying the healing process, the specific biological mechanisms that cause this disruption have remained elusive to both healthcare professionals and scientists alike.
The research project was co-led by NTU Associate Professor Guillaume Thibault from the School of Biological Sciences and Professor Kimberly Kline, a visiting professor from the University of Geneva at the Singapore Centre for Environmental Life Sciences and Engineering (SCELSE).
What sets E. faecalis apart from other bacteria is its method of causing harm. Instead of releasing toxins like many other pathogens do, E. faecalis generates a metabolic byproduct known as reactive oxygen species (ROS), which is detrimental to the healing of human skin cells.
The first author of the study, NTU Research Fellow Dr. Aaron Tan, discovered that E. faecalis employs a process called extracellular electron transport (EET) to continually produce hydrogen peroxide, a highly reactive form of oxygen that can damage living tissue. In the context of infected wounds, this bacterium emits hydrogen peroxide, leading to oxidative stress that harms human skin cells.
Laboratory experiments revealed that this oxidative stress triggers a defensive response in skin cells, particularly in keratinocytes, which play a vital role in skin repair. This response, known as the "unfolded protein response," helps cells manage damage by slowing down protein production and other essential functions, allowing for recovery. However, once activated, this stress response essentially immobilizes the cells, hindering their ability to migrate and close the wound—a crucial step in the healing process.
The research team further experimented with a genetically altered strain of E. faecalis that lacked the EET pathway. Remarkably, this strain produced considerably less hydrogen peroxide and did not impede wound healing. This finding underscored the significance of the metabolic pathway in the bacterium's capacity to disrupt skin repair.
To explore potential solutions, the researchers tested whether neutralizing hydrogen peroxide could counteract the damage done to skin cells. By applying catalase, a natural enzyme that breaks down hydrogen peroxide, to affected skin cells, they were able to reduce cellular stress and restore the cells' ability to migrate and heal effectively. This innovative approach offers a new avenue to combat antibiotic-resistant E. faecalis strains without relying solely on traditional antibiotics.
"Our research highlights that the very metabolism of the bacteria serves as the weapon, which was an unexpected finding for scientists," noted Assoc. Prof. Thibault, who also serves as the Assistant Dean for International Engagement at the College of Science.
"Rather than attempting to eradicate the bacteria using antibiotics—which is becoming increasingly challenging and may lead to further antibiotic resistance—we can now focus on neutralizing the harmful substances it produces, thereby promoting wound healing. Instead of attacking the source, we can directly target the underlying cause of chronic wounds: the reactive oxygen species."
This study establishes a direct connection between bacterial metabolism and the dysfunction of host cells, paving the way for a fresh therapeutic strategy for chronic wounds. The researchers propose that future wound dressings infused with antioxidants like catalase could serve as effective treatments, potentially transforming how we address these challenging medical conditions.
