Aminoglycosides with reduced ototoxicity

降低耳毒性的氨基糖苷类

基本信息

批准号：
9197240
负责人：
DEV PRIYA ARYA
金额：
$ 30万
依托单位：
NUBAD, LLC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9197240
关键词：
Address Adult Amikacin Amino Acids Amino Sugars Aminoglycosides Animal Model 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 Cessation of life Chemistry Clinical Communicable Diseases Complex Congresses Coupled Development Drug Design Drug resistance Enhancers Environment Gentamicins Green Fluorescent Proteins Growth Hair Cells Health Health Care Costs Human In Vitro Infection Institute of Medicine (U.S.)Larva Lead Libraries Link Marketing Measurement Medical Membrane Methods Modeling Mus Nosocomial Infections Organ Culture Techniques Parasites Parents Pathway interactions Peptides Pharmaceutical Preparations Phase Pigments Protein Biosynthesis Protocols documentation Pseudomonas aeruginosa RNA Renal function Research Research Institute Resistance Ribosomal RNA Ribosomes Sensory Hair Serum Solid South Carolina Staphylococcus aureus Structure Surgeon Testing Therapeutic Therapeutic Index Time Toxic effect Transgenic Organisms Translations United States United States National Academy of Sciences Universities Virus Work Zebrafish antimicrobial antimicrobial drug bacterial resistance biodefense cell injury combat cost design high throughput screening improved in vivo innovation lateral line method development microorganism multidisciplinary mutant neuromast novel ototoxicity pathogen promoter screening small molecule success

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 encompassing antibacterial screening and ototoxicity studies using zebrafish and guinea pig models, describes the development of 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 a zebrafish assay to identify conjugates that show reduced toxicities, opening possibilities for developing reduced toxicity RNA targeted aminosugar therapeutics.

项目摘要氨基糖苷是临床上最便宜，最著名的抗生素之一使用了70多年，但使用的主要局限性之一是耳毒性。我们正在开发快速和低成本的方法，以开发抗糖苷核糖体活动和降低毒性。在这个项目中，我们将确定小说氨基糖苷抗菌剂，表现出降低的耳毒性。彼此之间的复合物核糖体成分将被利用为小分子药物库的目标 - 使核糖体灭活，停止细菌蛋白质合成并引起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，并为解决这个问题的新颖解决方案提出了创造性的步骤。这里提出的工作是涵盖抗菌的多学科努力使用斑马鱼和豚鼠模型进行筛查和耳毒性研究，描述了作为无毒抗菌疗法的新型氨基加糖rRNA粘合剂的发展。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。我们建议使用斑马鱼测定法以识别偶联的人显示毒性降低，开辟了可能减少的可能性毒性RNA针对氨基加糖治疗剂。