Developing Non-Ototoxic Aminoglycosides

摘要： 氨基糖苷类（AG）抗生素由于其强效的抗肿瘤活性而在世界范围内被广泛使用。 抗菌活性和低成本。它们被广泛使用，尽管重要的一面 耳毒性和肾毒性效应。来自独立实验室的最新证据 表明AG在毛细胞中迅速积累，因为它们能够进入毛细胞， 这些细胞通过位于膜顶部附近的机电换能器通道， 静纤毛通道生物物理特性促进通过通道进入，但限制 通过同样的渠道退出。我们的数据清楚地表明，耳毒性可能是 通过阻止这些通道的进入来阻止。该提案的目标是发展 新的非耳毒性氨基糖苷类。我们的团队对生物物理学有着独特的见解， 机械门控通道的特性，并可以使用这些知识来设计 在空间上和/或电学上被限制进入通道的化合物 也就是毛细胞在AG骨架上选择修饰位点， 不干扰抗微生物活性。我们有能力调查 这些化合物在通道、细胞、终末器官、系统和整个动物水平， 使用电生理学、光学、分子和药理学手段来监测 耳毒性以及抗微生物活性。与这些发展相辅相成 化合物将鉴定AG进入内淋巴的机制 车厢一旦识别出这条途径，我们将设计出限制运输的方法 现有的AG，以便共同治疗计划可能会阻止AG访问MET 通道，从而限制进入毛细胞。本提案的重点是设计 治疗方案，无论是通过创建新的AG，或共同治疗计划，这将 改善AG给药引起的耳毒性。在拟议的两年期结束时， 在研究期间，我们将运用我们独特的知识基础和技能， 深入了解这些方法在降低耳毒性方面的有效性 导致AG。

Abstract: Aminoglycoside (AGs) antibiotics are used worldwide because of their potent antimicrobial activities and low cost. They are widely used despite the significant side effects of ototoxicity and nephrotoxicity. Recent evidence from independent laboratories demonstrated that AGs accumulate rapidly in hair cells because of their ability to enter these cells through the mechanoelectric transducer channel located near the tops of the stereocilia. Channel biophysical properties promote entry through the channel but limit exit through these same channels. Our data clearly show that ototoxicity can be prevented by blocking entry via these channels. The goal of this proposal is to develop novel non-ototoxic aminoglycosides. Our team has unique insights into the biophysical properties of the mechanically gated channels and can use this knowledge to design compounds that are sterically and/or electrically restricted from entering the channel and therefore the hair cell. Sites for modification are selected on the AG backbone so as not to interfere with antimicrobial activity. We have in hand the ability to investigate these compounds at the channel, cellular, end organ, system and whole animal level, using electrophysiological, optical, molecular and pharmacological means to monitor ototoxicity as well as antimicrobial activity. Complementary to the development of these compounds will be identifying the mechanism of entry of the AGs into the endolymph compartment. Upon identification of this pathway we will devise means to limit transport of existing AGs so that a co-treatment plan might prevent access of the AGs to the MET channel and thus limit entry into hair cells. The focus of this proposal is to design treatment regimes, either by creating novel AGs, or co-treatment plans, that will ameliorate ototoxicity due to AG administration. At the end of the proposed two-year research period, we will have applied our unique knowledge base and skill sets to gain insights into the effectiveness of either of these approaches in reducing ototoxicity caused AGs.