Phage-Based Therapeutics for Ocular Infections

基于噬菌体的眼部感染治疗

• 批准号: 10039252
• 负责人: Michelle C Callegan
• 金额: $ 18.13万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10039252
• 关键词: Acute; Address; Agonist; Anti-Inflammatory Agents; Antibiotic Resistance; Antibiotics; Bacillus; Bacteria; Bacterial Eye Infections; Bacterial Infections; Bacteriophages; Biology; Blindness; Cells; Centers for Disease Control and Prevention (U.S.); Clinic; Clinical; Combating Antibiotic Resistant Bacteria; Communicable Diseases; Cornea; Data; Drug Kinetics; Endophthalmitis; Engineering; Experimental Models; Eye; Eye Infections; Feasibility Studies; Goals; Growth; Health; Immune; In Vitro; Infection; Inflammation; Inflammatory; Keratitis; Klebsiella pneumoniae; LytA enzyme; Masks; Mediating; Modeling; Multi-Drug Resistance; Multiple Bacterial Drug Resistance; Mus; National Eye Institute; Nature; Organism; Parasites; Pathogenesis; Pathway interactions; Patients; Physicians; Positioning Attribute; Process; Production; Pseudomonas aeruginosa; Refractory; Regimen; Reporting; Research; Resistance; Retina; Speed; Staphylococcus aureus; Streptococcus pneumoniae; Testing; Therapeutic; Therapeutic Uses; Tissues; Toxic effect; Toxin; Traction; Translational Research; United States National Institutes of Health; Universities; Virulent; Vision; Visual Acuity; antimicrobial; base; clinically relevant; combat; efficacy testing; experimental study; falls; improved; improved outcome; in vivo; lysin; multi-drug resistant pathogen; novel; pathogen; pathogenic bacteria; preservation; prevent; programs; response; success; therapy outcome; treatment strategy

PROJECT SUMMARY / ABSTRACT Ocular bacterial infections cause a significant number of cases of blindness worldwide. Efforts to prevent damage to delicate ocular tissues during infection rely on swift and proper use of therapeutics to rapidly kill organisms and arrest damaging inflammation. Mainstay antibiotics currently approved for ocular use can kill ocular pathogens. However, given the speed at which these infections can evolve, the emergence of multidrug resistant (MDR) ocular pathogens, the delicate nature of ocular tissue, and the importance of proper visual acuity, halting these infections as soon as possible is critical to patients’ ocular health. Alternative antimicrobial strategies which result in rapid killing of organisms in the eye would provide a significant improvement over that of mainstay antibiotics which allow replication due to their slow activities, or antibiotics that are ineffective due to MDR pathogens. Bacteriophage-based therapeutics have gained traction as a last line experimental strategy for the treatment of patients infected with MDR pathogens. Efficacy testing of phages and, more recently, phage lysins, in treating bacterial infections is not new. However, their use in treating ocular infections of all types in a broad-spectrum regimen in eye infections has not been studied. Our goal is to create a phage lysin cocktail which can be administered to the eye during infection, resulting in rapid killing of those organisms, mitigation of inflammation, and preservation of vision. We hypothesize that because phage lysins rapidly lyse bacteria prior to phage exit, these lysins will rapidly kill bacteria in ocular tissues during infection. Preliminary data demonstrates feasibility and success in phage lysin-mediated killing of S. aureus in the eyes of mice. The next steps are to test the efficacy of phage lysins in killing other ocular bacterial pathogens in experimental models of keratitis and endophthalmitis (Aim 1), and then combine and test phage lysins of different bacteria in a broad-spectrum cocktail in these models against MDR pathogens (Aim 2). A critical barrier to clinical improvements in ocular bacterial infections is the use of mainstay antibiotics that may not kill efficiently enough. We have reported that regardless of the offending pathogen, bacterial replication in the eye triggers acute inflammation in response to an increasing innate immune agonist burden and results in toxin production which leads to tissue damage. These studies will determine whether phage lysins kill ocular pathogens more efficiently than mainstay antibiotics, resulting in improvements in therapeutic outcome. If effective, the next step is to test the phage lysin cocktails with innate pathway-based anti-inflammatory agents, which we are also pursuing. Testing of phage lysins in the treatment of ocular bacterial infections is novel, high-impact, translationally relevant, and will positively influence the ocular infectious disease field by identifying a more effective antimicrobial strategy for treating ocular infections, preventing blindness and benefitting patients afflicted with these infections.

项目摘要/摘要 眼部细菌感染导致全世界相当数量的失明病例。努力实现 预防感染期间对脆弱的眼组织的损害有赖于迅速和正确地使用治疗药物 迅速杀死生物体，阻止破坏性炎症。目前批准用于眼科的主要抗生素 使用可以杀死眼部病原体。然而，考虑到这些感染的演变速度，出现 多药耐药(MDR)眼部病原体的种类、眼组织的微妙性质以及 正确的视力，尽快阻止这些感染对患者的眼睛健康至关重要。备择 能够迅速杀死眼睛中的有机体的抗菌策略将提供显著的 对主要抗生素的改进，后者由于其缓慢的活性而允许复制，或抗生素 由于多药耐药病原体而无效。 以噬菌体为基础的疗法已经作为一种最后的实验策略获得了吸引力 多药耐药病原体感染患者的治疗。噬菌体的效力测试，以及最近的噬菌体 赖氨酸在治疗细菌感染方面并不新鲜。然而，它们在治疗所有类型的眼部感染中的使用 广谱疗法治疗眼部感染的研究尚未见报道。我们的目标是创造一种噬菌体裂解酶鸡尾酒 在感染期间可以用在眼睛上，导致这些微生物迅速死亡，缓解 炎症和视力保护。我们推测是因为噬菌体溶血素能迅速溶解 细菌在噬菌体离开之前，这些溶血素将在感染期间迅速杀死眼组织中的细菌。 初步数据显示噬菌体裂解酶在眼部杀灭金黄色葡萄球菌的可行性和成功 老鼠的世界。下一步是测试噬菌体赖氨酸在杀死其他眼部细菌病原体方面的效果。 角膜炎和眼内炎的实验模型(目标1)，然后结合和检测噬菌体裂解酶 不同细菌在这些模型中的广谱鸡尾酒中对抗多药耐药病原体(目标2)。 眼部细菌感染的临床改善的一个关键障碍是使用Mainstant 杀伤力可能不够强的抗生素。我们已经报道过，无论致病的病原体是什么， 眼部细菌复制引发急性炎症反应先天免疫激动剂增多 负担和结果是产生毒素，从而导致组织损伤。这些研究将确定 噬菌体赖氨酸比主要抗生素更有效地杀灭眼部病原体，从而改善了 治疗结果。如果有效，下一步是测试基于天然途径的噬菌体裂解蛋白鸡尾酒。 消炎剂，这也是我们正在追求的。噬菌体溶血素检测在眼科治疗中的应用 细菌感染是新的、高影响的、与翻译相关的，并将对 寻找更有效的眼部抗菌药物治疗眼部感染性疾病 感染，预防失明，使患有这些感染的患者受益。