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）：由于其有效的抗菌活性和低成本，全世界使用了氨基糖苷（AGS）抗生素。尽管耳毒性和肾毒性具有显着的副作用，但它们被广泛使用。来自独立实验室的最新证据表明，AGS在毛细胞中迅速积累，因为它们能够通过位于立体尾核的顶部的机械电换能器通道进入这些细胞。通道生物物理特性促进通过通道进入，但通过这些相同的通道限制了出口。我们的数据清楚地表明，可以通过通过这些渠道阻止进入进入，可以防止耳毒性。该建议的目的是开发新型的非毒性氨基糖苷。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，可以利用这些知识来设计在空间和/或电限制进入通道的化合物，从而使毛细胞。选择用于修饰的位点在AG骨架上选择，以免干扰抗菌活性。我们可以使用电生理学，光学，分子和药理学手段来监测耳毒性以及抗菌活性，在通道，细胞，末端器官，系统和整个动物水平上研究这些化合物的能力。这些化合物的开发的补充将确定AG进入内淋巴舱的机制。在确定此途径后，我们将设计方法来限制现有AG的运输，以便共同处理计划可能会阻止AG进入MET通道，从而限制进入毛细胞的进入。该提案的重点是通过创建新颖的AG或共同处理计划来设计治疗方案，从而改善由于AG给药而减轻耳毒性。在拟议的为期两年的研究期结束时，我们将应用我们的独特知识库和技能集，以深入了解这两种方法在降低耳毒性导致AG中的有效性。 公共卫生相关性：尽管耳毒性发病率很高，但在全球范围内最广泛使用的抗生素。我们已经表明，听觉毛细胞对AG敏感，因为它们的Ag摄取率很高，这是由于AG经过位于立体胶体顶部的新型机械敏感离子通道的能力而产生的。我们的计划是设计新的抗生素，这些抗生素在空间和/或电气上限制通过该通道。结合这种方法，我们将确定AG进入内淋巴解决方案的机制，并设计制定负责任的运输机制的共同计划，从而阻止AGS到达其渗透的离子通道。