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Dual-Wavelength Blue Light Irradiation for Improved Treatment of Staphylococcus aureus Infections

双波长蓝光照射改善金黄色葡萄球菌感染的治疗

基本信息

批准号：
10724476
负责人：
Tianhong Dai
金额：
$ 20.88万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-18 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10724476
关键词：
Abscess Acinetobacter baumannii Affect Animals Antibiotic Resistance Antibiotic Therapy Antibiotics Antimicrobial Resistance Antioxidants Attention Bacteria Biological Carotenoids Cells Clinic Clinical Community-Acquired Infections Cutaneous DNA Damage Development Effectiveness Elderly Endothelial Cells Epithelial Cells Exhibits Exposure to Fibroblasts Foundations Genetic Engineering Health Hospitalization Human Immune In Vitro Incidence Individual Infection Inflammatory Response Interruption Light Microbial Biofilms Mus Myoblasts Needles Neisseria gonorrhoeae Optics Oxidative Stress Penetration Phagocytes Photobleaching Photosensitizing Agents Pigments Predisposition Prevalence Production Prophylactic treatment Protocols documentation Pseudomonas aeruginosa Reactive Oxygen Species Regimen Reporting Resistance development Resistance profile Safety Site Staphylococcus aureus Staphylococcus aureus infection Testing Tetracyclines Therapeutic Time Tissues Toxic effect Translating Treatment Cost Treatment Protocols Virulent alternative treatment antimicrobial antimicrobial tolerance bactericide bioluminescence imaging cytotoxic cytotoxicity effectiveness evaluation efficacy evaluation genotoxicity improved innovation interstitial irradiation keratinocyte lens methicillin resistant Staphylococcus aureus mortality novel pathogen pathogenic bacteria preclinical study real time monitoring resistant strain safety study staphyloxanthin wound healing

项目摘要

PROJECT SUMMARY/ABSTRACT Staphylococcus aureus is a leading cause of infections worldwide. In recent decades, the treatment of S. aureus infections has become increasingly difficult because of the increasing incidence of antibiotic resistance, justifying the need for developing alternative therapeutics. Antimicrobial blue light (aBL; 405 nm wavelength), an innovative nonpharmacological approach, has attracted increasing attention due to its intrinsic activity against a wide range of bacteria irrespective of their antibiotic resistance profiles. However, it has also been found that S. aureus is much more tolerant of 405 nm aBL than most other bacteria. A potential reason for the higher tolerance of S. aureus to aBL is the presence of staphyloxanthin (STX) in S. aureus. STX acts as an antioxidant and facilitates the tolerance of S. aureus to oxidative stress generated by 405 nm aBL. Fortunately, a recent study discovered that STX is prone to photobleaching by 460 nm wavelength irradiation. This finding leads to our central hypothesis that 460 nm irradiation would potentiate the susceptibility of S. aureus to killing by 405 nm aBL. To test this hypothesis, we propose two Specific Aims: In Aim 1, we will first investigate the efficacy of the dual-wavelength irradiation (DWI; 460 nm followed by 405 nm) strategy for killing S. aureus in vitro. A panel of S. aureus isolates, including ATCC reference strains and recent clinical isolates, will be selected. Both planktonic bacteria and biofilms will be studied. We will also assess the effect of the pre-application of 460 nm irradiation on the 405 nm aBL-induced production of reactive oxygen species in S. aureus. Additionally, as the safety study, we will evaluate the cytotoxicity and genotoxicity of DWI to normal human cells by treating human cells under therapeutic exposures of DWI for eradicating S. aureus. Finally, we will determine whether DWI affects the ROS-producing capability of the immune cells. In Aim 2, we will conduct a preclinical study to determine the efficacy and safety of DWI for treating cutaneous S. aureus abscesses in mice. We will use a bioluminescent strain of methicillin-resistant S. aureus (MRSA USA 300) to infect mice, thus allowing real-time monitoring of the extent of infection in living animals using bioluminescence imaging. DWI will be initiated at varying time points (30 min, 4 h, or 48 h) after infection. To facilitate light penetration in biological tissues, we will use a novel optical lens-microneedle array patch to deliver light interstitially to the infection sites. The efficacy found with DWI will be compared with that of systemic tetracycline, an empirical antibiotic therapy in clinic for cutaneous S. aureus infections. As the safety study, we will determine the effects of DWI on the viability and DNA damage of the host cells, wound healing, and inflammatory response in treated tissues. Collectively, the successful completion of the Specific Aims outlined in this application will provide the foundation required to determine the effectiveness and safety of DWI for treating localized S. aureus infections; and will help establish protocols for the use of this innovative strategy.

项目总结/文摘