The ribosome is one of the major targets for antibiotics. Multi-drug resistant pathogens are making our current arsenal of ribosome-targeting antibiotics obsolete, highlighting the need for development of new antimicrobial compounds.
Ongoing project
Here we focus on discovering novel ribosometargeting antibiotics with improved activity and selectivity, with chemical scaffolds that target novel sites on the ribosome and different steps of the translation cycle.
Specifically, we propose to (WP1) develop 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; (WP2) develop proline-rich antimicrobial peptides as novel antimicrobial agents by taking advantage of available high resolution ribosome structures and their ease of synthesis and modification; (WP34) utilise high-throughput screening to discover compounds with novel chemical scaffolds that have activity against new cellular targets, such as the (WP3) ribosome rescue systems, and (WP4) stringent response pathways in bacteria.
The consortium aims to characterise the mechanism of action of novel antimicrobial agents as well as their in vivo and in vitro efficacy, in particular against Priority 1 pathogens and Mycobacterium tuberculosis.
Project partners
- Daniel Wilson, University of Hamburg, Germany (Coordinator)
- C. Axel Innis, Institut Européen de Chimie et Biologie, France
- Erik Böttger, University of Zurich, Switzerland
- Vasili Hauryliuk, Umeå University, Sweden
- Reynald Gillet, Université de Rennes, France
- Dominik Rejman, The Czech Academy of Sciences, Czech Republic
- Marco Scocchi, University of Trieste, Italy
Popular summary
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.
Publications
- International Journal of Molecular Sciences, 2020. Characterization of Cetacean Proline-Rich Antimicrobial Peptides Displaying Activity against ESKAPE Pathogens
- J Med Chem, 2020. Peptide Inhibitors of Bacterial Protein Synthesis with Broad Spectrum and SbmA-Independent Bactericidal Activity against Clinical Pathogens.
- ACS Infect Dis, 2020. Aminoglycosides: Time for the Resurrection of a Neglected Class of Antibacterials?
- Nucleic Acids Res, 2020. Reassembling green fluorescent protein for in vitro evaluation of trans-translation.
- PNAS, 2020. A widespread toxin-antitoxin system exploiting growth control via alarmone signaling
- Nature Reviews Microbiology, 2020. Target protection as a key antibiotic resistance mechanism
- bioRxiv, 2020. Structural basis of resistance to lincosamide, streptogramin A, and pleuromutilin antibiotics by ABCF ATPases in Gram-positive pathogens
- Molecular Cell, 2020. Structural Basis for Bacterial Ribosome-Associated Quality Control by RqcH and RqcP
- ChemMedChem, 2019. Proline-Rich Peptides with Improved Antimicrobial Activity against E. coli, K. pneumoniae, and A. baumannii.
- ACS Infect Dis, 2019. Modification at the 2′-Position of the 4,5-Series of 2-Deoxystreptamine Aminoglycoside Antibiotics To Resist Aminoglycoside Modifying Enzymes and Increase Ribosomal Target Selectivity.
- Medchemcomm, 2019. Synthesis, ribosomal selectivity, and antibacterial activity of netilmicin 4′-derivatives.
- Bioorg Med Chem, 2019. Synthesis and evaluation of 1,3,4-oxadiazole derivatives for development as broad-spectrum antibiotics.
- Talanta, 2019. Analysis of nucleotide pools in bacteria using HPLC-MS in HILIC mode.
