Riboswitches as new antibacterial targets

核糖开关是主要存在于细菌mRNA分子的5 '-非翻译区的RNA元件。在与小的代谢物，如糖衍生物和维生素的选择性相互作用后，它们调节作为这些分子的生物合成途径的组分的基因的表达。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致病菌生长所必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开发。微生物病原体的耐药性菌株的不断增加进一步强调了鉴定、探索和验证抗生素干预的新靶点的必要性。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，验证和表征靶向细菌核糖开关的化合物。下一个阶段将建立在我们确定的代谢物类似物，已被证明可以调节glmS-核糖开关和硫盒核糖开关的功能，分别。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，我们将继续鉴定具有改进活性的已鉴定化合物的衍生物。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标。

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.