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.

项目摘要氨基糖苷是最便宜，最著名的抗生素之一临床用途已有70多年了，但使用的主要限制之一是耳毒性。我们正在开发快速和低成本的方法来开发具有抗核糖体活性并降低毒性的氨基糖苷。在这个项目中，我们将确定新型的氨基糖苷抗菌剂，显示出降低的耳毒性。核糖体成分之间的复合物将被用作小的目标分子药物库会使核糖体灭活，停止细菌蛋白合成并导致细菌死亡，同时降低毒性。这项工作解决了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解决这个问题的新颖解决方案。这里提出的工作是使用miRNA结合的多学科工作，抑制方法，结合使用抗菌筛查和使用耳毒性研究豚鼠模型描述了一种快速方法的发展和验证将新型的氨基加糖rRNA粘合剂作为无毒抗菌治疗剂。这拟议工作的成功将是当前可用的重要补充抗菌疗法的方法。我们建议使用新型氨基糖苷修改和获得专利的NUBAD分析，以识别显示降低的共轭物毒性，开辟了开发靶向RNA靶向疗法的可能性，并减少毒性。