Aminoglycosides with reduced ototoxicity via miRNA targeting

通过 miRNA 靶向降低耳毒性的氨基糖苷类药物

基本信息

批准号：
9891947
负责人：
DEV PRIYA ARYA
金额：
$ 39.77万
依托单位：
NUBAD, LLC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-15 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9891947
关键词：
Address Adult Amino Acids Amino Sugars Aminoglycosides Animal Model Animals Anti-Bacterial Agents Antibiotic Resistance Antibiotics Antimicrobial Resistance Auditory Auditory Brainstem Responses Awareness Bacteria Bacterial Infections Bacterial Proteins Binding Biological Assay Books Boston CBA/J Mouse Cavia Centers for Disease Control and Prevention (U.S.)Cessation of life Chemistry Clinical Communicable Diseases Complex Congresses Coupled Development Drug Design Drug resistance Escherichia coli Growth Hair Cells Health Health Care Costs In Vitro Infection Institute of Medicine (U.S.)Kanamycin Lead Legal patent Libraries Link Measurement Medical Methods MicroRNAs Modeling Modernization Modification Mus Neomycin Nosocomial Infections Organ Culture Techniques Parasites Parents Pathway interactions Peptides Pharmaceutical Preparations Phase Pigments Protein Biosynthesis Protocols documentation Pseudomonas aeruginosa RNA Renal function Research Resistance Ribosomal RNA Ribosomes Role Sensory Hair Serum Solid South Carolina Streptomycin Structure Surgeon Testing Therapeutic Therapeutic Index Time Tobramycin Toxic effect Translations United States United States National Academy of Sciences Universities Validation Virus Work aminoglycoside-induced ototoxicity antibiotic resistant infections antimicrobial antimicrobial drug bacterial resistance base biodefense combat cost design follow-up high throughput screening improved in vivo innovation method development microorganism multi-drug resistant pathogen multidisciplinary mutant novel ototoxicity screening small molecule success targeted treatment

项目摘要

PROJECT SUMMARY Aminoglycosides are one of the cheapest and well-known antibiotics in clinical use for over 70 years, but one of the major limitations in their use is their ototoxicity. We are developing fast and low cost methods to develop aminoglycosides with anti- ribosomal activities and reduced toxicity. In this project, we will identify novel aminoglycoside antibacterials, that show reduced ototoxicity. Complexes between ribosomal components will be exploited as targets for small molecule drug libraries that- inactivate the ribosome, stopping bacterial protein synthesis and causing bacterial death while reducing toxicity. This work addresses an important health issue, antibiotic ototoxicity, and presents creative steps towards a novel solution to this problem. The work proposed here, a multidisciplinary effort using a miRNA binding and inhibition approach, coupled with antibacterial screening and ototoxicity studies using guinea pig models, describes the development and validation of a rapid way to generate novel aminosugar rRNA binders as non-toxic antibacterial therapeutics. The success of the proposed work would be a significant addition to currently available approaches in antibacterial therapy. We propose using novel aminoglycoside modifications and patented NUBAD assays to identify conjugates that show reduced toxicities, opening possibilities for developing RNA targeted therapeutics with reduced toxicity.

项目概要氨基糖苷类药物是最便宜且众所周知的抗生素之一临床使用已有 70 多年的历史，但其使用的主要限制之一是其耳毒性。我们正在开发快速、低成本的开发方法具有抗核糖体活性并降低毒性的氨基糖苷类药物。在这个项目中，我们将鉴定新型氨基糖苷类抗菌药物，其耳毒性降低。核糖体成分之间的复合物将被用作小分子的靶标分子药物库——使核糖体失活，阻止细菌蛋白质合成并导致细菌死亡，同时降低毒性。这项工作地址一个重要的健康问题，抗生素耳毒性，并提出了创造性的步骤这个问题的一个新颖的解决方案。这里提出的工作是一项多学科努力，利用 miRNA 结合和抑制方法，结合抗菌筛选和耳毒性研究豚鼠模型，描述了一种快速方法的开发和验证产生新型氨基糖 rRNA 结合剂作为无毒抗菌疗法。这拟议工作的成功将是对现有工作的重大补充抗菌治疗的方法。我们建议使用新型氨基糖苷类药物修饰和获得专利的 NUBAD 测定来识别显示减少的缀合物毒性，为开发RNA靶向疗法提供了可能性毒性。