Exploration of the TPP riboswitch as a new target for antibiotics
In this project, we will explore the TPP riboswitch as a new drug target for antibiotics for key ESKAPE pathogens (E. coli, K. pneumoniae, A. baumannii, P. aeruginosa, S. aureus) and Streptococcus pneumoniae. The TPP riboswitch has already been validated as a drug target, however, potent and drug-like ligands with antibiotic activity are needed as starting points to develop novel strategies for anti-infective treatments. The goal of this proposal is to deliver such compounds. Using an innovative assay technology, we will develop a high-throughput assay that monitors simultaneously transcription efficiency and the regulatory activity of the riboswitch, which is crucial for its action, and use this assay to screen the CZ- and EU-OPENSCREEN libraries of lead-like compounds. The hits obtained will be thoroughly validated and the most promising hits will be optimised to improve their affinity. The advanced compounds will be evaluated for antibiotic activity against the key ESKAPE pathogens and Streptococcus pneumoniae. We will also assess the broad-spectrum potential of the compounds and carry out mode of action studies to ensure that the compounds act on target. If the TPP riboswitch holds up to its high promises, this project will pave the way for urgently needed new antibiotics.
- Ruth Brenk, University of Bergen, Norway (Coordinator)
- Petr Bartunek, Institute of Molecular Genetics of the ASCR, Czech Republic (Partner)
- Matthias Mack, Mannheim University of Applied Sciences, Germany (Partner)
- Gints Smits, Latvian Institute of Organic Synthesis, Latvia (Partner)
- Daniel Lafontaine, Université de Sherbrooke, Canada (Observer)
The antibiotics we are currently using are losing effectiveness due to the emergence of resistant bacteria. Therefore, there is an urgent need to develop new antibiotics. In this project, we aim to develop ligands for an RNA element (a so-called riboswitch), that controls the expression of essential bacterial genes. These ligands can then serve as starting points for drug discovery for future antibiotics. To reach this goal, we have assembled a team of highly skilled researchers from Norway, the Czech Republic, Latvia, Germany, and Canada. Together, we are developing a test system so that we can screen thousands of molecules for binding to the target. Subsequently, the identified ligands will be optimized to increase their affinity. The advanced compounds will be evaluated for antibiotic activity against the key bacteria for which new antibiotics are urgently needed. We will also carry out mode-of-action-studies to ensure that the compounds act on target as intended. If investigated riboswitch holds up to its high promises, this project will pave the way for urgently needed new antibiotics.