Development of Novel Ophthalmic Antibiotics

新型眼科抗生素的开发

基本信息

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
项目类别：
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

项目摘要

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。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Assessment of Keratitis Severity Using Quantitative Image Analysis in an In Vivo Murine Model of Staphylococcus aureus Bacterial Keratitis.

DOI：
10.1167/tvst.11.11.12
发表时间：
2022-11-01
期刊：
TRANSLATIONAL VISION SCIENCE & TECHNOLOGY
影响因子：
3
作者：
Meijome, Tomas E.;Wozniak, Rachel;Kang, Linda;Azzouz, Lyna;Niziol, Leslie M.;Johnson, William L.;Kriegel, Matthias;Woodward, Maria A.
通讯作者：
Woodward, Maria A.

Efficacy of a Novel Ophthalmic Antimicrobial Drug Combination Toward a Large Panel of Staphylococcus aureus Clinical Ocular Isolates From Around the World.

新型眼科抗菌药物组合对来自世界各地的大量金黄色葡萄球菌临床眼部分离株的功效。

DOI：
10.1097/ico.0000000000002414
发表时间：
2020
期刊：
Cornea
影响因子：
2.8
作者：
Laskey,Emily;Chen,Yimin;Sohn,MichaelB;Gruber,Emma;Chojnacki,Michaelle;Wozniak,RachelAF
通讯作者：
Wozniak,RachelAF

Antimicrobial Activity of a Triple Antibiotic Combination Toward Ocular Pseudomonas aeruginosa Clinical Isolates.

DOI：
10.1167/tvst.11.5.26
发表时间：
2022-05-02
期刊：
TRANSLATIONAL VISION SCIENCE & TECHNOLOGY
影响因子：
3
作者：
Mei, Jia A.;Johnson, William;Kinn, Bailey;Laskey, Emily;Nolin, Lydia;Bhamare, Pratham;Stalker, Charlotte;Dunman, Paul M.;Wozniak, Rachel A. F.
通讯作者：
Wozniak, Rachel A. F.

Anterior Segment Optical Coherence Tomography in Ocular Argyrosis.