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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.

项目摘要氨基糖苷类抗生素是临床上最便宜、最知名的抗生素之一使用超过70年，但其使用的主要限制之一是其耳毒性。我们正在开发快速和低成本的方法来开发具有抗- 核糖体活性和降低的毒性。在这个项目中，我们将确定新的氨基糖苷类抗菌药物，其显示降低的耳毒性。之间复合体核糖体组分将被用作小分子药物文库的靶标，破坏核糖体，停止细菌蛋白质合成，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，对这个问题的一个新的解决方案。这里提出的工作，一个多学科的努力，包括抗菌使用斑马鱼和豚鼠模型的筛选和耳毒性研究，描述了开发新型氨基糖rRNA结合剂作为无毒抗菌治疗剂。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。我们建议使用斑马鱼检测来识别显示出降低的毒性的缀合物，为开发降低的毒性RNA靶向氨基糖治疗剂。