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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：
10219273
负责人：
Michelle C Callegan
金额：
$ 21.1万
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 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219273
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 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.

项目总结/摘要眼部细菌感染在世界范围内导致大量失明病例。努力在感染期间防止对脆弱的眼组织的损伤依赖于迅速和适当地使用治疗剂，迅速杀死有机体并阻止破坏性炎症。目前批准用于眼部的主要抗生素使用可以杀死眼部病原体。然而，考虑到这些感染的发展速度，多药耐药（MDR）眼部病原体，眼部组织的脆弱性，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。替代导致快速杀死眼睛中的生物体的抗微生物策略将提供显著的相对于主要抗生素的改进，主要抗生素由于其缓慢的活性而允许复制，或抗生素因为MDR病原体而无效。基于噬菌体的治疗方法已经获得了牵引力，作为治疗癌症的最后一线实验策略。治疗感染MDR病原体的患者。抗病毒药物的功效测试，以及最近的噬菌体溶素用于治疗细菌感染并不新鲜。然而，它们在治疗各种类型的眼部感染中的用途是不确定的。尚未研究眼感染的广谱治疗方案。我们的目标是创造一种噬菌体溶素鸡尾酒其可以在感染期间施用于眼睛，导致快速杀死那些生物体，缓解以及视力的保护。我们假设由于噬菌体溶素快速溶解在噬菌体离开之前，这些溶素将在感染期间迅速杀死眼组织中的细菌。初步数据表明噬菌体溶素介导的S.眼睛金黄色对小鼠下一步是测试噬菌体溶素在杀死其他眼部细菌病原体中的功效，实验模型的角膜炎和眼内炎（目的1），然后联合收割机和测试噬菌体溶素在这些模型中，广谱混合物中的不同细菌对抗MDR病原体（目标2）。眼部细菌感染临床改善的一个关键障碍是使用Mastrial 抗生素可能不能有效地杀死。我们已经报道过，不管是什么病原体，眼内细菌复制触发急性炎症，以响应增加的先天免疫激动剂负担并导致毒素产生，从而导致组织损伤。这些研究将确定是否噬菌体溶素比主流抗生素更有效地杀死眼部病原体，从而改善治疗效果如果有效的话，下一步是用基于先天途径的噬菌体溶素鸡尾酒来测试。抗炎药，我们也在研究。噬菌体溶素治疗眼部疾病的测试细菌感染是新的，高影响，预防相关，并将积极影响通过鉴定治疗眼部感染性疾病的更有效的抗微生物策略预防失明并使患有这些感染的患者受益。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Roles of CCL2 and CCL3 in intraocular inflammation during Bacillus endophthalmitis.

DOI：
10.1016/j.exer.2022.109213
发表时间：
2022-11
期刊：
EXPERIMENTAL EYE RESEARCH
影响因子：
3.4
作者：
Mursalin, Md Huzzatul;Astley, Roger;Coburn, Phillip S.;Miller, Frederick C.;Callegan, Michelle C.
通讯作者：
Callegan, Michelle C.