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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：
9982540
负责人：
DEV PRIYA ARYA
金额：
$ 4.49万
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 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9982540
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 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 off-patent 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.

项目总结