Reconstitution of Bacterial Targets in Model Membranes for a Biosensor-based Functional Analysis and Screening of Antibiotics

重建模型膜中的细菌靶标，用于基于生物传感器的功能分析和抗生素筛选

基本信息

批准号：
77063697
负责人：
Professor Dr. Gerd Bendas
金额：
--
依托单位：
Pharmazeutische und Medizinische Chemie
依托单位国家：
德国
项目类别：
Research Units
财政年份：
2008
资助国家：
德国
起止时间：
2007-12-31 至 2009-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/77063697?language=en
关键词：
Reconstitution Bacterial Targets Model Membranes

项目摘要

A large number of antibiotics exert their activity by interacting with bacterial cell membranes or targets therein. The prototype lantibiotic nisin combines two killing mechanisms in one molecule, inhibition of cell wall biosynthesis and formation of specific membrane pores. For both it uses the cell wall precursor lipid II as a target and anchor molecule. We introduce a planar model membrane system to simulate the antibiotic activity of compounds and to interpret their mode of action. Two combined biosensors, quartz crystal microbalance (QCM) and cyclic voltammetry (CV) allow to follow the target binding of and membrane permeabilization by antibiotics in real time, either simultaneously or separately. The detection of kinetic binding constants (QCM) can validate the role of certain membrane targets, such as C55P, C55PP, lipid I and lipid II. Isothermal titration calorimetry measurements will supplement the binding data. CV studies of pore formation will be completed by atomic force microscopy. The investigations with nisin will be extended to a series of lantibiotics to delineate structure-activity relationships within this class of antibiotics. Furthermore, these techniques will be applied to other compounds from the consortium (especially lipopeptides, such as daptomycin, friulimicin or empedopeptin) to study for membrane targets and the mode of action. The biosensor based analysis of structurefunction correlations of dual action antibiotics will give directions for the design of innovative antiinfectives.

大量抗生素通过与细菌细胞膜或靶标相互作用来发挥其活性。原型盐酰化尼我们在一个分子中结合了两种杀伤机制，抑制细胞壁生物合成和特定膜孔的形成。对于两者，它都使用细胞壁前体脂质II作为靶标和锚分子。我们引入了平面模型膜系统，以模拟化合物的抗生素活性并解释其作用方式。两个合并的生物传感器，石英晶体微量平衡（QCM）和环状伏安法（CV），可以同时或分别或分别或分别或分别地实时遵循抗生素的靶标结合和膜通透性。动力学结合常数（QCM）的检测可以验证某些膜靶标的作用，例如C55P，C55PP，脂质I和脂质II。等温滴定量热法测量将补充结合数据。孔形成的简历研究将通过原子力显微镜完成。对尼生蛋白的研究将扩展到一系列甘西生酰生物，以描绘这类抗生素中的结构活性关系。此外，这些技术将应用于联盟（尤其是lipopepides，例如Daptomycin，friulimicin或apepopeptin）的其他化合物，以研究膜靶标和作用方式。基于生物传感器的双重作用抗生素结构功能相关性的分析将为设计创新抗感染的设计提供指示。