Developing Non-Ototoxic Aminoglycosides

开发非耳毒性氨基糖苷类药物

• 批准号: 8225109
• 负责人: Anthony J Ricci
• 金额: $ 19.99万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8225109
• 关键词: Adverse effects; Aminoglycoside Antibiotics; Aminoglycosides; Animal Model; Animals; Antibiotics; Auditory; Binding; Biochemical; Biochemical Pathway; Biological Assay; Cells; Chemical Structure; Cochlea; Cochlear duct; Collaborations; Complex; Data; Databases; Development; Effectiveness; Endolymph; FDA approved; Gentamicins; Goals; Hair Cells; Hand; Image; Imaging Techniques; Incidence; Ion Channel; Knowledge; Laboratories; Modification; Molecular; Monitor; Nephrotoxic; Optics; Pathway interactions; Property; Research; Research Personnel; Resistance; Ribosomes; Site; Site-Directed Mutagenesis; Solutions; Specificity; Stereocilium; Structure; Testing; Texas red; Tissues; Transducers; Treatment Protocols; Vertebral column; aminoglycoside-induced ototoxicity; antimicrobial; base; body system; cell type; chemical property; cost; design; insight; knowledge base; nephrotoxicity; novel; ototoxicity; prevent; programs; research study; skills; success; therapy design; tissue culture; treatment planning; two-photon; uptake

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Aminoglycosides (AGs) are the most widely used antibiotics worldwide, despite having a high incidence of ototoxicity. We have shown that auditory hair cells are sensitive to AGs because of their high rate of AG uptake, arising from the ability of AGs to pass through a novel mechanosensitive ion channel located at the tops of the stereocilia. Our plan is to design new antibiotics that are sterically and/or electrically restricted from passing through this channel. In conjunction with this approach we will identify the mechanism by which AGs enter the endolymph solution and devise a cotreatment plan to block the responsible transport mechanism, thus preventing the AGs from reaching the ion channel that they permeate.

描述（由申请人提供）：氨基糖苷类（AG）抗生素因其强效抗菌活性和低成本而在全球范围内使用。它们被广泛使用，尽管有显著的耳毒性和肾毒性副作用。来自独立实验室的最新证据表明，AG在毛细胞中迅速积累，因为它们能够通过位于静纤毛顶部附近的机电换能器通道进入这些细胞。通道生物物理性质促进通过通道的进入，但限制通过这些相同的通道的退出。我们的数据清楚地表明，耳毒性可以通过阻断这些通道来预防。本提案的目标是开发新型非耳毒性氨基糖苷类药物。我们的团队对机械门控通道的生物物理特性有独特的见解，并可以利用这些知识来设计空间和/或电限制进入通道并因此进入毛细胞的化合物。在AG骨架上选择修饰位点，以免干扰抗微生物活性。我们有能力在通道，细胞，终末器官，系统和整个动物水平上研究这些化合物，使用电生理，光学，分子和药理学手段监测耳毒性以及抗菌活性。这些化合物的开发的补充将是确定AG进入内淋巴室的机制。在鉴定该途径后，我们将设计限制现有AG运输的方法，以便共同治疗计划可以防止AG进入MET通道，从而限制进入毛细胞。该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，这将改善耳毒性由于AG管理。在拟议的两年研究期结束时，我们将运用我们独特的知识基础和技能，深入了解这两种方法在减少AG引起的耳毒性方面的有效性。 公共卫生相关性：氨基糖苷类（AG）是全球使用最广泛的抗生素，尽管耳毒性发生率很高。我们已经表明，听觉毛细胞是敏感的AG，因为他们的高速率的AG摄取，所产生的能力的AG通过一个新的mechanosensitive离子通道位于顶部的静纤毛。我们的计划是设计新的抗生素，这些抗生素在空间和/或电学上受到限制，不能通过这个通道。结合这种方法，我们将确定AGs进入内淋巴溶液的机制，并设计一个cotreatment计划，以阻止负责任的运输机制，从而防止AGs到达离子通道，他们渗透。