Development of Novel Ophthalmic Antibiotics

新型眼科抗生素的开发

• 批准号: 10407570
• 负责人: Rachel A F Wozniak
• 金额: $ 14.9万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10407570
• 关键词: Address; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Biological; Biological Assay; Blindness; CRISPR interference; Catheters; Cell Death; Cells; Chemicals; Clinical; Cornea; Coupled; Data; Development; Development Plans; Disease; Doctor of Philosophy; Essential Genes; Experimental Designs; Eye Infections; FDA approved; Fluoroquinolones; Formulation; Generations; Goals; Growth; Industry; Infection; Intellectual Interest; Keratitis; Kinetics; Knowledge; Laboratories; Lead; Libraries; Lung infections; Mediating; Mentorship; Microbial Biofilms; Modeling; Molecular; Moxifloxacin; Mus; Outcome; Pathogenesis; Pathway interactions; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Polymyxin B; Process; Property; Pseudomonas aeruginosa; Reagent; Reporter; Reporting; Research; Research Technics; Resistance; Resistance development; Rifampin; Severity of illness; Staphylococcus aureus; Structure-Activity Relationship; Suppressor Genes; System; Systemic infection; Therapeutic; Tissues; Topical application; Training; Training Programs; Trimethoprim; Vision; Visual; Work; Work Ethic; Wound Infection; adenylate kinase; advanced system; antimicrobial; antimicrobial drug; bactericide; base; career development; cellular targeting; design; drug development; drug discovery; efficacy study; human disease; improved; in vivo; knock-down; member; mouse model; novel; novel drug class; progenitor; programs; scaffold; screening; skills; small molecule; small molecule libraries; success; therapeutic development; tool; Address; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Biological; Biological Assay; Blindness; CRISPR interference; Catheters; Cell Death; Cells; Chemicals; Clinical; Cornea; Coupled; Data; Development; Development Plans; Disease; Doctor of Philosophy; Essential Genes; Experimental Designs; Eye Infections; FDA approved; Fluoroquinolones; Formulation; Generations; Goals; Growth; Industry; Infection; Intellectual Interest; Keratitis; Kinetics; Knowledge; Laboratories; Lead; Libraries; Lung infections; Mediating; Mentorship; Microbial Biofilms; Modeling; Molecular; Moxifloxacin; Mus; Outcome; Pathogenesis; Pathway interactions; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Polymyxin B; Process; Property; Pseudomonas aeruginosa; Reagent; Reporter; Reporting; Research; Research Technics; Resistance; Resistance development; Rifampin; Severity of illness; Staphylococcus aureus; Structure-Activity Relationship; Suppressor Genes; System; Systemic infection; Therapeutic; Tissues; Topical application; Training; Training Programs; Trimethoprim; Vision; Visual; Work; Work Ethic; Wound Infection; adenylate kinase; advanced system; antimicrobial; antimicrobial drug; bactericide; base; career development; cellular targeting; design; drug development; drug discovery; efficacy study; human disease; improved; in vivo; knock-down; member; mouse model; novel; novel drug class; progenitor; programs; scaffold; screening; skills; small molecule; small molecule libraries; success; therapeutic development; tool

ABSTRACT Bacterial keratitis is a vision threatening disease and contributes significantly to world blindness. Given the severity of the disease, immediate, broad spectrum antibiotics such as fourth generation fluoroquinolones are crucial for successful treatment. However, rising resistance coupled with limited industry-driven drug development highlights the need for novel ophthalmic antimicrobial therapeutics. The central goals of this proposal are to address the antimicrobial void through the development of novel ophthalmic antibiotics. Preliminary data has demonstrated the promise of rifampicin+polymyxin B/trimethoprim (PT), a combination of FDA-approved antibiotics that displays broad-spectrum, synergistic activity with reduced propensity to develop resistance. A central goal of this proposal is to advance rifampicin+PT with in vivo efficacy studies in order to move this combination toward the FDA’s 505 (B)2 fast track approval process. However given the quickening pace of antibiotic resistance, novel classes of drugs must also be concurrently developed. In that regard, a high throughput chemical library screen for novel, first-in-class agents with activity against Pseudomonas aeruginosa and Staphylococcus aureus, the most common causes of keratitis, has been initiated and initial lead compounds identified. Importantly, the screening paradigm is designed to identify compounds with anti-biofilm activity, a growth state that is notoriously challenging to eradicate in human disease including ocular infections, and has not previously been the target of high throughput drug discovery screens. As part of hit-to-lead prioritization, biologic and physiochemical studies will be performed, a CRISPR-interference essential gene knock down strain set will be created in order to facilitate the identification of cellular targets of lead compounds, and a mouse model of keratitis will be established. These latter two tool systems directly enable the proposed research but also have wide-ranging utility with respect to understanding essential genes/pathways in keratitis pathogenesis. This research program provides advanced training in drug discovery that will simultaneously define the clinical promise of rifampicin+PT, identify novel agents that kill biofilm-associated cells and develop high yield tools for antimicrobial or pathogenesis studies. In addition, this proposal details a career development plan for Dr. Rachel Wozniak, MD, PhD in order to facilitate her transition to independence. Dedicated mentorship, course work and specialized seminars will contribute to an expanding knowledge of experimental design and advanced research techniques. She has obtained full institutional and departmental support for these endeavors had has demonstrated the necessary skill set, work ethic and intellectual curiosity necessary for success.

抽象的 细菌性角膜炎是一种威胁疾病的视力，对世界失明产生了重大贡献。 鉴于该疾病的严重程度，直接，广谱抗生素，例如第四代 氟喹诺酮对于成功治疗至关重要。但是，阻力增加加上有限的 行业驱动的药物开发强调了对新型眼科抗菌治疗的需求。 该提案的核心目标是通过发展来解决抗菌空隙 新型眼科抗生素。初步数据证明了利福平+多性粘肽的希望 B/甲氧苄啶（PT），FDA批准的抗生素的组合，显示广谱， 协同活性，倾向降低了抗药性。该提议的核心目标是 通过体内效率研究提高利福平+PT，以将这种组合转移到 FDA的505（b）2快速批准过程。但是考虑到抗生素的加快速度 耐药性，新型药物也必须同时发展。在这方面，高 吞吐量化学库屏幕，用于针对假单胞菌活性的新颖，一流的代理 铜绿和金黄色葡萄球菌是角膜炎的最常见原因，已经开始，并且 鉴定的初始铅化合物。重要的是，筛选范式旨在识别 具有抗生物膜活性的化合物，这种生长状态众所周知，对放射线构成挑战 包括眼感染在内的人类疾病，以前不是高通量的靶标 药物发现屏幕。作为命中至领先优先级的一部分，生物学和生理学研究将 要执行，将创建一个CRISPR干扰基因敲除应变集，以便为了 促进识别铅化合物的细胞靶标，而角膜炎的小鼠模型将 建立。这些后来的两个工具系统直接使拟议的研究能够 广泛的效用有关了解角膜炎发病机理中的基本基因/途径。 该研究计划提供了药物发现的高级培训，该培训将简单地定义 利福平+pt的临床承诺，确定杀死生物膜相关细胞的新型药物和 开发用于抗菌或发病机理研究的高产工具。此外，该建议详细介绍了 为了促进她的过渡 独立。专门的精通制度，课程工作和专业下水道将有助于 扩展实验设计和高级研究技术的知识。她已经获得了 对这些努力的全部机构和部门的支持已经证明了必要的 成功所需的技能，职业道德和智力好奇心。