Aminoglycosides with reduced ototoxicity via miRNA targeting

项目总结 氨基糖苷类抗生素是世界上最便宜、最知名的抗生素之一。 临床使用超过70年，但使用它们的主要限制之一是它们 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化合物。在这个项目中， 我们将寻找新的氨基糖苷类抗菌药，显示出降低耳毒性的作用。 核糖体成分之间的复合体将被开发为小分子 分子药物文库--使核糖体失活，阻止细菌蛋白质 在减少毒性的同时，合成并导致细菌死亡。这部作品的主题是 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，以 解决这个问题的新办法。 这里提出的工作是一项多学科的努力，使用miRNA结合和 抑制方法，结合使用抗菌筛选和耳毒性研究 豚鼠模型，描述了一种快速开发和验证的方法 产生新的氨基糖rRNA结合剂作为无毒的抗菌药物。这个 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药物 改进和获得专利的NUBAD分析以确定显示减少的结合物 毒性，为开发RNA靶向治疗药物提供了可能性 毒性。

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.