Aminoglycosides with reduced ototoxicity

项目摘要 氨基糖苷类抗生素是临床上最廉价、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。

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.