RNA structures as targets for antimicrobial compounds

Regulatory RNA structures play an important role for pathogens. Many virulence-related genes encode a temperature-sensitive mRNA element, a so-called RNA thermometer (RNAT) in their transcript. Upon entry into a warm-blooded host, this RNAT structure melts open, allowing translation of the downstream gene. The virulence regulator PrfA of Listeria monocytogenes is controlled by such an RNAT. Further important RNA structures can be found in RNA viruses, such as the viral frameshift element. The viral frameshift element leads to a frameshift during translation, allowing different expression ratios of viral polyproteins located in the ORF1a and ORF1ab open reading frames. Disturbing this ratio of frameshifting, severely cripples coronavirus replication. Due to the importance of RNA structures for virulence, targeting by antimicrobial compounds could be a suitable alternative to classical protein-targeting antibiotics. By different Förster Resonance Energy Transfer (FRET) approaches we will screen a library aiming to identify compounds altering RNA structures. As a proof-of-concept approach, we have used aminoglycosides and validated their inhibitory effect on viral translation by a dual-luciferase reporter system. Furthermore, we could observe a reduction of viral infection by determining the viral titer after infection. Therefore, targeting RNA structures seems to be a promising way to treat clinically relevant infections.