Exploration of the TPP riboswitch as a new target for antibiotics

Acronyme EXPLORE
Call JPI-EC-AMR Joint Transnational Call for Proposals 2018 
Implementation period 01.04.2019. – 31.03.2022.
Project coordinator Prof. Ruth Brenk, University of Bergen, Norway
Project partners Mannheim University of Applied Sciences, Germany
Université de Sherbrooke, Quebec, Canada
Latvian Institute of Organic Synthesis, Latvia
CZ-OPENSCREEN, Institute of Molecular Genetics, ASCR, Prague, Czech Republic
Leader of Latvian team Dr. Gints Šmits
Total costs 1 188 358 EUR
Costs for Latvian partner
104 500 EUR


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. To reach this goal, we have assembled a team of highly skilled researchers from Norway, the Czech Republic, Latvia, Germany, and Canada, who are experts in riboswitch biology, microbiology, compound screening, structure-based drug design, organic synthesis and medicinal chemistry. 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 optimized 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.