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.

项目摘要/摘要金黄色葡萄球菌是全球感染的主要原因。近几十年来，治疗S。由于抗生素抗性的发生率增加，金黄色葡萄球菌感染变得越来越困难证明需要开发替代治疗剂的必要性。抗菌蓝光（ABL； 405 nm波长），一种创新的非药理学方法，由于其内在活性而引起了人们的关注与多种细菌相比，无论其抗生素耐药性概况如何。但是，也已经发现金黄色葡萄球菌的耐受性比大多数其他细菌更为405 nm。潜在的原因金黄色葡萄球菌对ABL的耐受性较高是金黄色葡萄球菌中葡萄糖糖果（STX）的存在。 STX充当抗氧化剂并促进金黄色葡萄球菌对405 nm ABL产生的氧化应激的耐受性。幸运的是，最近的一项研究发现，STX容易受到460 nm波长辐射的光漂白。这个发现导致我们的核心假设，即460 nm辐射会增强金黄色葡萄球菌的敏感性杀死405 nm abl。为了检验这一假设，我们提出了两个具体目的：在AIM 1中，我们将首先研究双波长照射的功效（DWI； 460 nm，然后是405 NM）在体外杀死金黄色葡萄球菌的策略。金黄色葡萄球菌分离株，包括ATCC参考菌株和将选择最近的临床分离株。将研究浮游细菌和生物膜。我们也会评估460 nm辐照预先应用对405 nm ABL诱导的反应性产生的影响金黄色葡萄球菌中的氧气。此外，作为安全研究，我们将评估细胞毒性和遗传毒性通过在DWI的治疗暴露下治疗人类细胞以消除S.通过治疗人类细胞。金黄色葡萄酒。最后，我们将确定DWI是否影响免疫细胞的ROS产生能力。在AIM 2中，我们将进行一项临床前研究，以确定DWI治疗皮肤的功效和安全性 S.小鼠的金黄色葡萄球菌脓肿。我们将使用耐甲氧西林的生物发光菌株（MRSA 美国300）要感染小鼠，从而可以实时监测活体动物的感染程度生物发光成像。感染后，DWI将在不同的时间点（30分钟，4小时或48小时）开始。到促进生物组织中的光渗透，我们将使用一种新型的光学镜头微透明阵列贴片在内部传递光线到感染部位。 DWI发现的功效将与全身性四环素，一种皮质链球菌感染的诊所的经验抗生素疗法。作为安全研究，我们将确定DWI对宿主细胞的活力和DNA损伤的影响，伤口愈合，和处理的组织中的炎症反应。总的来说，本申请中概述的特定目标的成功完成将提供确定DWI治疗局部金黄色链球菌感染的有效性和安全所需的基础；并将帮助建立使用这种创新策略的协议。