Development of novel ribosome-targeting antibiotics

• Daniel Wilson, University of Hamburg, Germany (Coordinator)
• C. Axel Innis, Institut Européen de Chimie et Biologie, France (Partner)
• Erik Böttger, University of Zurich, Switzerland (Partner)
• Vasili Hauryliuk, Umeå University, Sweden (Partner)
• Reynald Gillet, Université de Rennes, France (Partner)
• Dominik Rejman, The Czech Academy of Sciences, Czech Republic (Partner)
• Marco Scocchi, University of Trieste, Italy (Observer)

Multi-drug resistant pathogens are making our current arsenal of ribosome-targeting antibiotics obsolete, highlighting the need for development of new antimicrobial compounds. The RIBOTARGET consortium aims to discover novel ribosome-targeting antibiotics with improved activity and selectivity against Priority 1 pathogens and Mycobacterium tuberculosis, with chemical scaffolds that target novel sites on the ribosome and different steps of the translation cycle. This includes development of (i) novel aminoglycoside antibiotics with potent antibacterial activity and improved target selectivity to overcome the toxicity that is associated with this clinically important class of antibiotics; (ii) proline-rich antimicrobial peptides as novel antimicrobial agents by taking advantage of available high resolution ribosome structures and their ease of synthesis and modification, as well as (iii-iv) utilizing high-throughput screening to discover compounds with novel chemical scaffolds that have activity against new cellular targets, such as the (iii) ribosome rescue systems, and (iv) stringent response pathways in bacteria. To achieve these aims our multi-interdisciplinary RIBOTARGET consortium brings together leading scientists with complementary expertise in microbiology, biochemistry, chemical synthesis and structural biology. This will enable us to characterize the mechanism of action of novel antimicrobial agents as well as their in vivo and in vitro efficacy.

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