Designing new aminoglycosides to alleviate inner ear toxicity

 性状（由申请人提供）：氨基糖苷类是一种广泛使用的广谱抗生素。这些化合物的主要副作用是耳（和前庭）和肾毒性。在R21奖项期间获得的数据表明，这些化合物通过体外专门的机械敏感离子通道进入内耳的感觉毛细胞。利用我们对机械转导通道的生物物理特性的独特知识，再加上由鉴定细菌核糖体上的氨基糖苷类相互作用位点的晶体学数据提供的见解，我们开发了新型化合物，大大降低了体内的耳毒性和肾毒性，尽管在抗微生物活性的广度上付出了一些代价。这些原理验证实验是迭代设计新化合物的基础。设计组件有三个阶段，首先使用初始屏幕作为起点， 西索米星上的取代基，以试图更好地分离抗菌活性和毒副作用。其次，我们将合成和测试一个新的修饰位点的基础上，从实验中产生的新数据对庆大霉素衍生物。最后，我们将改变母体化合物，以更好地靶向特定的微生物，如假单胞菌。我们已经开发了测试每种化合物纯度和特异性的能力。我们可以探测 在体内和体外模型中的抗菌功能以及耳毒性和肾毒性。我们还可以测试对阻力发展的敏感性和前庭病变。这种基于新假设的迭代能力应该会产生一类新的无毒抗生素。

 DESCRIPTION (provided by applicant): Aminoglycosides are a widely used broad spectrum antibiotic. A major side effect of these compounds is oto- (and vestibulo) and nephrotoxicity. Data obtained during an R21 award demonstrates that these compounds enter sensory hair cells of the inner ear via a specialized mechanosensitive ion channel in vitro. Using our unique knowledge of the biophysical properties of the mechanotransduction channel coupled with insights provided by crystallography data that identifies aminoglycoside interacting sites on the bacterial ribosome, we have developed novel compounds that greatly reduced oto- and nephrotoxicity in vivo, though at some cost to the breadth of antimicrobial activity. These proof-of-principal experiments serve as the basis for iteratively designing new compounds. The design component has three phases, first to use our initial screen as a starting point where we will alter the substituted group on sisomicin to try to better separate antimicrobial activity and the toxic side effects. Second we will synthesize and test a novel modification site based on new data arising from experiments on gentamicin derivatives. Finally, we will change the parent compound to better target specific microbes such as Pseudomonas organisms. We have developed the ability to test for purity and specificity of each compound. We can probe activity in terms of antimicrobial function as well as oto- and nephrotoxicity in in vivo and in vitro models. We can also test for sensitivity to the development of resistance and for vestibular pathologies. Together this iterative ability based on a novel hypothesis should yield a new class of nontoxic antibiotics.