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

• 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
• 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

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 氨基糖苷类抗生素是最便宜和众所周知的抗生素之一， 临床使用已超过70年，但其使用的主要局限性之一是其 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毒性的氨基糖苷类。在这个项目中， 我们将鉴定新的氨基糖苷类抗菌药物，其显示降低的耳毒性。 核糖体组分之间的复合物将被利用作为小分子的靶点。 分子药物库，它可以抑制核糖体，阻止细菌蛋白质 合成并导致细菌死亡，同时降低毒性。这项工作涉及 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， 一个新的解决方案。 这里提出的工作，一个多学科的努力，使用一个miRNA的结合， 抑制方法，加上抗菌筛选和耳毒性研究，使用 豚鼠模型，描述了一种快速的方法， 产生作为无毒抗菌治疗剂的新型氨基糖rRNA结合剂。的 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 改进和专利NUBAD检测，以鉴定显示降低的 毒性，为开发RNA靶向治疗开辟了可能性， 毒性