Phage-Based Therapeutics for Ocular Infections

基于噬菌体的眼部感染治疗

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要眼部细菌感染导致全世界大量失明病例。防止感染期间脆弱的眼组织受损，依靠迅速和正确使用治疗方法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，但是，考虑到这些感染的发展速度，其出现。多重耐药 (MDR) 眼部病原体、眼部组织的脆弱性质以及适当的视力，尽快阻止这些感染对于患者的眼部健康至关重要。导致快速杀死眼内微生物的抗菌策略将提供显着的效果。优于主要抗生素（由于其活性缓慢而允许复制）或抗生素由于 MDR 病原体而无效。基于噬菌体的疗法作为最后一线实验策略已获得关注。感染 MDR 病原体的患者的治疗，以及噬菌体的功效测试。溶素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应用。尚未研究眼部感染的广谱治疗方案。我们的目标是创造噬菌体溶素混合物。可以在感染期间将其施用于眼睛，从而快速杀死这些微生物，缓解我们勇敢地面对这一点，因为噬菌体溶酶会迅速裂解。在噬菌体退出之前，这些溶素会在感染过程中迅速杀死眼组织中的细菌。初步数据证明噬菌体溶素介导杀死眼内金黄色葡萄球菌的可行性和成功下一步是测试噬菌体溶素杀死其他眼部细菌病原体的功效。角膜炎和眼内炎的实验模型（目标1），然后结合并测试噬菌体溶素在这些针对 MDR 病原体的模型中，使用广谱混合物中的不同细菌（目标 2）。眼部细菌感染临床改善的一个关键障碍是使用主要药物我们报告说，无论致病病原体如何，抗生素都可能不足以有效杀死它们。眼睛中的细菌复制会引发急性炎症，以响应不断增加的先天免疫激动剂这些研究将确定是否会产生毒素并导致组织损伤。噬菌体溶素比主要抗生素更有效地杀死眼部病原体，从而改善如果有效，下一步是使用基于先天途径的噬菌体溶素混合物进行测试。抗炎剂，我们也在研究噬菌体溶素在眼部治疗中的应用。细菌感染是新颖的、高影响力的、转化相关的，并将积极影响通过确定更有效的治疗眼部感染的抗菌策略，在眼部感染性疾病领域取得进展感染，预防失明并使受这些感染影响的患者受益。