Riboswitches as new antibacterial targets

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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.