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Riboswitches as new antibacterial targets

核糖开关作为新的抗菌靶点

基本信息

批准号：
77063780
负责人：
Professor Dr. Günter Mayer
金额：
--
依托单位：
Life and Medical Sciences Institute (LIMES)
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 2015-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/77063780?language=en
关键词：
Riboswitches new antibacterial targets

项目摘要

Riboswitches are RNA elements mainly found in the 5’-untranslated region of bacterial mRNA molecules. Upon selective interaction with small metabolites, such as sugar-derivatives and vitamins, they regulate the expression of genes that are components of the biosynthetic pathways of these molecules. Riboswitches thus make use of a fundamentally new mechanism to control gene expression in bacteria. Since they have been shown to regulate the expression of essential genes necessary for growth of pathogenic bacteria they represent a potential target class for the development of new antibiotics, albeit being largely unexplored yet. The increasing appearance of antibiotic-resistant strains of microbial pathogens further emphasizes the necessity to identify, explore and validate novel targets for antibiotic intervention. Riboswitches provide such a new target class. Our project aims at the identification, validation, and characterization of compounds that target bacterial riboswitches. The next period will build upon our identified metabolite-analogues that have been shown to modulate the function of glmS-riboswitches and thi-box-riboswitches, respectively. We will further analyse their impact on riboswitch function in vivo and most importantly on bacterial growth. Moreover, we will continue to identify derivatives of the identified compounds with improved activities. We will use these compounds for studying the biochemistry, secondary structure, and structural dynamics of riboswitches from pathogenic bacteria and to validate riboswitches as true antibacterial targets.

核糖开关是主要存在于细菌 mRNA 分子 5'-非翻译区的 RNA 元件。通过与糖衍生物和维生素等小代谢物选择性相互作用，它们调节作为这些分子生物合成途径组成部分的基因的表达。因此，核糖开关利用一种全新的机制来控制细菌中的基因表达。由于它们已被证明可以调节病原菌生长所需的必需基因的表达，因此它们代表了开发新抗生素的潜在目标类别，尽管在很大程度上尚未被探索。微生物病原体耐药菌株的不断出现进一步强调了识别、探索和验证抗生素干预新靶点的必要性。核糖开关提供了这样一个新的目标类别。我们的项目旨在鉴定、验证和表征针对细菌核糖开关的化合物。下一阶段将建立在我们确定的代谢物类似物的基础上，这些代谢物类似物已被证明可以分别调节 glmS-核糖开关和 thi-box-核糖开关的功能。我们将进一步分析它们对体内核糖开关功能的影响，最重要的是对细菌生长的影响。此外，我们将继续鉴定已鉴定化合物的具有改进活性的衍生物。我们将使用这些化合物来研究病原菌核糖开关的生物化学、二级结构和结构动力学，并验证核糖开关作为真正的抗菌靶点。