Molecular Basis for Antibiotic Specificity

描述（由申请人提供）： 氨基糖苷类是用于治疗几种细菌感染的药物，这些细菌感染是生物恐怖主义的潜在因子。它们的治疗价值来源于它们特异性识别原核16S rRNA A位点并干扰蛋白质合成的能力。本提案的目的是确定决定氨基糖苷类药物对原核生物与真核生物A位点特异性的分子力，以及研究线粒体是否具有这种特异性。A位点是这些药物的靶点。与后一个靶点的结合被认为是氨基糖苷类药物治疗相关不良反应的基础。此外，将采用基于荧光的方法来评价氨基糖苷类结合对rRNA A位点构象动力学的影响，以测试将药物诱导的rRNA构象变化作为药物引起异常翻译能力的关键因素的模型。这些研究将揭示氨基糖苷类抗生素原核生物特异性的关键决定因素，并增强我们对氨基糖苷类抗生素抑制蛋白质合成的分子机制的理解。这一信息对于未来抗生素设计的合理基础的发展是有价值的。

DESCRIPTION (provided by applicant): Aminoglycosides are drugs used in the treatment of several bacterial infections that are potential agents of bioterrorism. Their therapeutic value is derived from their ability to specifically recognize prokaryotic 16S rRNA A-sites and interfere with protein synthesis. The goal of this proposal is to define the molecular forces that dictate the specificities of aminoglycosides for prokaryotic versus eukaryotic A-sites, as well as to investigate whether mitochondria! A-sites serve as targets for these drugs. Binding to the latter target has been implicated for the basis of the adverse effects associated with aminoglycoside treatment. In addition, a fluorescent-based approach will be employed to evaluate the impact of aminoglycoside binding on the conformational dynamics of rRNA A-sites to test the model that invokes a drug-induced conformational change in the rRNA as being a key factor in the ability of the drugs to cause aberrant translation. The proposed studies will reveal critical determinants for the prokaryotic specificity of aminoglycosides, as well as enhance our understanding of molecular mechanism by which aminoglycosides inhibit protein synthesis. This information is valuable for the development of a rational basis for future antibiotic design.