NTU Singapore's Breakthrough in Understanding Bacterial Sabotage of Wound Healing

Researchers at Nanyang Technological University (NTU) Singapore have made a pivotal discovery in the fight against chronic wound infections. Their study, published in Science Advances, uncovers how Enterococcus faecalis (E. faecalis), a common bacterium in stubborn wounds, actively suppresses the host's immune response and repair processes. Unlike typical pathogens that deploy toxins, E. faecalis employs a metabolic trick—generating reactive oxygen species (ROS) through extracellular electron transport (EET)—to induce oxidative stress in skin cells, halting their migration and prolonging infections.

This finding is particularly relevant for Singapore, where over 16,000 cases of chronic wounds, including diabetic foot ulcers, pressure injuries, and venous leg ulcers, occur annually, especially among the aging population and diabetes patients. Globally, diabetic foot ulcers affect 18.6 million people yearly, often leading to amputations due to persistent bacterial interference. The NTU team's work offers hope through non-antibiotic strategies, aligning with Singapore's push for innovative healthcare solutions amid rising antimicrobial resistance.

Chronic Wounds: A Growing Challenge in Singapore and Beyond

Chronic wounds fail to heal within three months, creating biofilms where bacteria like E. faecalis thrive. In diabetic patients, poor circulation and neuropathy exacerbate the issue, with E. faecalis isolated in up to 70% of wound infections. Singapore's multiethnic population sees an incidence of 0.43% for wound treatments, with diabetic ulcers comprising a significant portion.

These wounds impose heavy burdens: economic costs exceed millions in treatments, and complications like amputations affect quality of life. NTU's research highlights why standard antibiotics often fail—E. faecalis persists by disrupting host repair rather than direct invasion. For higher education, this underscores NTU's leadership in translational microbiology, training students for roles in research jobs tackling public health crises.

Enterococcus faecalis: The Opportunistic Pathogen Profile

E. faecalis, part of the gut microbiome, becomes problematic in immunocompromised hosts. It's notorious for antibiotic resistance, especially vancomycin-resistant strains (VRE), complicating wound care. In chronic settings like diabetic foot ulcers, it forms biofilms shielding it from immune cells and drugs.

NTU studies show E. faecalis doesn't just colonize; it manipulates the environment. Previous work from the Kline lab at SCELSE (Singapore Centre for Environmental Life Sciences Engineering) revealed its immune evasion in urinary tract infections, now extended to wounds. Prevalence in Singapore wounds mirrors global trends, emphasizing the need for NTU-like innovations.

Unraveling the Mechanism: Redox Metabolism Meets Host Stress

The core discovery: E. faecalis's EET pathway exports electrons, producing superoxide that dismutates to hydrogen peroxide (H₂O₂). This ROS diffuses into keratinocytes, causing lipid peroxidation and endoplasmic reticulum (ER) stress.

ER stress activates the unfolded protein response (UPR), a survival pathway via sensors like IRE1 and PERK. UPR splices XBP1 mRNA, upregulates chaperones like BiP, and halts translation to refold proteins. However, hyperactivation paralyzes cells: keratinocytes stop migrating, fibroblasts slow proliferation, delaying closure.

Step-by-Step: How E. faecalis Derails Wound Repair

1. Bacterial Colonization: E. faecalis enters wounds, forms biofilms.
2. EET Activation: Under aerobic conditions, flavin-mediated EET generates extracellular ROS.
3. Oxidative Assault: H₂O₂ penetrates host cells, peroxidizes lipids.
4. UPR Trigger: ER detects misfolded proteins, activates IRE1/PERK/ATF6 arms.
5. Cellular Paralysis: Reduced migration (scratch assays show 50% delay), inflammation skews to chronic state.
6. Persistent Infection: Healing stalls, risking amputation.

NTU confirmed via mutants: ΔEET strains produce less ROS, no UPR, normal healing.

Photo by National Institute of Allergy and Infectious Diseases on Unsplash

NTU's Rigorous Experimental Approach

The team used HaCaT keratinocytes in scratch assays, MOI 600 infections. qPCR tracked UPR markers (XBP1s, CHOP); immunoblotting confirmed. Transposon screens identified EET mutants. Mouse excisional wounds showed delayed closure with wild-type vs. mutants. Catalase (100 U/ml) rescued migration by 80%.

Single-cell RNA-seq from prior datasets enriched UPR/oxidative genes in infected keratinocytes. This multi-omics validation exemplifies NTU's state-of-the-art facilities, ideal for aspiring research scientists.

A Game-Changing Treatment: Catalase and Antioxidant Dressings

Catalase decomposes H₂O₂ to water/oxygen, neutralizing ROS without bactericidal effects. In vitro, it suppressed UPR, restored migration. Exogenous H₂O₂ mimicked wild-type impairment in mutants.

Practical: Infuse commercial dressings (e.g., hydrogels) with catalase—safe, FDA-approved. Avoids resistance, complements debridement/topicals. NTU plans animal trials; Assoc Prof Thibault notes: "The bacteria’s metabolism is the weapon."

Implications for Singapore's Healthcare Landscape

With diabetes prevalence at 13.7% (projected 1M cases by 2030), NTU's advance could cut amputations (500+/year). Aligns with MOH's antimicrobial stewardship. SCELSE's role boosts interdisciplinary training, positioning NTU grads for Singapore higher ed jobs.

Expert Timothy Barkham (Tan Tock Seng Hospital): "Promising new direction beyond antibiotics."

NTU's Leadership in Microbiology and Infectious Diseases Research

NTU's School of Biological Sciences and SCELSE pioneer host-pathogen interactions. Prof Kline's lab unravels E. faecalis virulence; Thibault's focuses on ER stress. This builds on prior works like immune modulation in polymicrobial infections.

Facilities: Optical Bio-Imaging Centre enables advanced imaging. Attracts global talent, fostering PhD/postdoc opportunities via higher-ed-jobs/postdoc.

Career Pathways in Wound Healing and Microbiology Research

• Research Assistants: Lab work on biofilms, ROS assays.
• PhD Students: Host-microbe dynamics at NTU/SCELSE.
• Clinicians: Wound care specialists integrating antioxidants.
• Industry: Biotech firms developing dressings; check higher-ed-jobs/faculty or research-jobs.

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Photo by National Cancer Institute on Unsplash

Future Outlook: From Bench to Bedside

NTU eyes clinical trials for catalase dressings. Broader: Target EET inhibitors? Explore UPR modulators. Singapore's RIE2030 funds such innovations. Impacts: Reduced healthcare costs, better outcomes for diabetics.

Explore higher-ed-career-advice for thriving in such fields.

Why This Matters for Higher Education and Innovation in Singapore

NTU exemplifies how university research drives national health security. Students gain hands-on experience in high-impact projects, preparing for university jobs and beyond. As antibiotic resistance surges, such breakthroughs position Singapore as a biotech hub.

Discover opportunities at higher-ed-jobs, rate-my-professor, and higher-ed-career-advice.