Riboswitches as new antibacterial targets

• Antragsteller: Professor Dr. Günter Mayer
• Fachliche Zuordnung: Biochemie
• Förderung: Förderung von 2008 bis 2016
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 33421847

• Erstellungsjahr: 2019

Zusammenfassung der Projektergebnisse

Riboswitches are RNA elements located in the 5’untranslated regions of bacterial mRNA molecules. These RNA elements selectively recognize metabolites upon which the expression of the adjacent gene, which encodes proteins and enzymes involved in the respective metabolite’s metabolism, is inhibited. These riboswitch structures represent potential target sites for antibacterial compounds, as some of them regulate the expression of essential genes. This characteristic of riboswitches nurtured the idea to generate compounds that resemble the riboswitch activating properties but do not share the metabolite’s biological function. The glmS riboswitch, which is activated by the metabolite glucosamine-6-phosphate regulates the expression of an enzyme that is essential for the biosynthesis of precursors of the bacterial cell wall. We generated and validated compounds that act on the glmS riboswitch. The administration of one of these compounds, namely carba-glucosamine (cGlcN), was found to lead to the inhibition of the growth of bacteria. The analysis of the mode of action of cGlcN suggests that it is taken up and phosphorylated by the phosphoenolpyruvate-sugar transport system gamP. This in vivo activation leads to a downregulation of the glmS mRNA and consequently to the induction of cell wall biosynthesis stress. Eventually, inhibition of bacterial growth of Bacillus subtilis and Staphylococcus aureus was observed. This study validates the glmS riboswitch as a suitable antibacterial target structure and opens the path towards identifying and developing other compound classes as antibiotics, which exert antibacterial activity by selective targeting of RNA structures in riboswitches.

Projektbezogene Publikationen (Auswahl)

• (2010). Cyclohexane compounds and their use as antibiotics. EP 10 194 929.5 (PCT/EP2011/072597)
  Lünse CE, Schmidt MS, Wittmann V, Mayer G
  
• (2011).Carba-sugars activate the glmS-riboswitch from Staphylococcus aureus. ACS Chem. Biol., 6, 675-678
  Lünse CE, Schmidt M, Wittmann V, Mayer G
  
• (2014). Novel TPP-riboswitch activators bypass metabolic enzyme dependency. Front. Chem., 2, 53
  Lünse CE, Scott FJ, Suckling CJ, Mayer G
  
• (2014). Screening assays to identify artificial glmS ribozyme activators. Meth. In Mol. Biol., Springer Protocols, Humana Press Ltd. (Ed. Lafontaine)
  Lünse CE, Mayer G
  
• (2014). The promise of riboswitches as potential antibacterial drug targets. Int. J. Med. Microbiol., 304, 79-92
  Lünse CE, Schüller A, Mayer G
  
• (2017). Activation of the glmS ribozyme confers bacterial growth inhibition. ChemBioChem. 2; 18(5):435-440
  Schüller A, Matzner D, Lünse C. E, Wittmann V, Schumacher C, Unsleber S, Brötz-Oesterhelt H, Mayer C, Bierbaum G, Mayer G
  
• (2017). Fluoro-carba-sugars are glycomimetic activators of the glmS ribozyme. Chemistry. 12; 23(51):12604-12612
  Matzner D, Schüller A, Seitz T, Wittmann V, Mayer G
  
• (2017). Reporter gene-based screening for TPP riboswitch activators. Methods Mol Biol.; 1520:227-235
  Lünse CE, Mayer G