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Development of novel ribosome-targeting antibiotics

English title Development of novel ribosome-targeting antibiotics
Applicant Böttger Erik Christian
Number 185777
Funding scheme Joint Programming Initiative on Antimicrobial Resistance (JPIAMR)
Research institution Institut für Medizinische Mikrobiologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Infectious Diseases
Start/End 01.03.2020 - 31.08.2022
Approved amount 289'000.00
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Keywords (7)

Ribosome; Translation; Aminoglycosides; Antibiotic; RelA; proline-rich antimicrobial peptides; tmRNA

Lay Summary (German)

Lead
Multi-drug resistant pathogens are making our current arsenal of ribosome-targeting antibiotics obsolete, highlighting the need for development of new antimicrobial compounds.
Lay summary

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) 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.

Direct link to Lay Summary Last update: 11.12.2018

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Abstract

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. Here we focus on discovering novel ribosome-targeting 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 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; 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; utilize high-throughput screening to discover compounds with novel chemical scaffolds that have activity against new cellular targets, such as the ribosome rescue systems, and stringent response pathways in bacteria. To achieve these aims our multiinterdisciplinary consortium brings together leading scientists with complementary expertise in microbiology, biochemistry, chemical synthesis and structural biology. This will enable usto characterize 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.
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