Targeting Bacterial T-Box and SAM Riboswitches by Rational Drug Design Approaches (RIBODESIGN)

• Applicants: Dr. Fabian Barthels; Dr. Christian Kersten; Privatdozentin Dr. Wilma Ziebuhr
• Subject Area: Pharmacy
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 584376531

Antibiotic resistant pathogens are an emerging global threat. One of the highest risk pathogens according to the world health organization (WHO) priority list is methicillin-resistant Staphylococcus aureus (MRSA). In our project, we will target non-coding RNA (ncRNA) elements, which are essential for S. aureus survival and virulence. RNA-targeting small molecules are a novel therapeutic strategy gaining momentum from the drug approval of Risdiplam in 2020. Especially riboswitches, which are found in many procaryotes, but not in humans, are a promising drug target for the development of antibiotics with novel modes of action. These non-coding RNAs regulate transcription or translation of essential metabolites in the bacteria. The targets of interest described herein, are the T-Box riboswitch that controls de novo methionine synthesis, and the SAM-I riboswitch which regulates S-adenosylmethionine (SAM) metabolism in S. aureus. In our approach we will transfer strategies from rational drug design that are usually applied to protein targets, to RNA-targeting taking advantage of our previous experience in computational and medicinal chemistry, microbiology, RNA- ligand development and RNA-mediated gene regulation studies. The results from this work will not only serve as a proof-of-concept for rational development of RNA-targeting small molecules with antibiotic properties in general, but also establish a pipeline for the development of further potential RNA-targeting antibiotics. Our methods cover in silico, in vitro and in cellulo techniques, which allows performance of whole design-make-test-analyze cycles of early drug discovery and hit identification/optimization. Identified lead structures may hold the potential of further in vivo investigation and development.

• DFG Programme: Research Grants