4'-O-substitutions determine selectivity of aminoglycoside antibiotics
| Autor: | Venki Ramakrishnan, Ng Chyan Leong, Déborah Perez-Fernandez, Erik C. Böttger, Rashid Akbergenov, Pia Thommes, Stefan Duscha, Pietro Freihofer, Kathrin Lang, Iwona Kudyba, Rashmi Patak, Heithem Boukari, Andrea Vasella, Dmitri Shcherbakov, Swapna Vaddi, Martin Meyer, Srinivas Reddy Dubbaka, Tanja Matt |
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| Přispěvatelé: | University of Zurich, Vasella, Andrea |
| Rok vydání: | 2013 |
| Předmět: |
Male
Staphylococcus aureus medicine.drug_class Antibiotics Molecular Sequence Data Mycobacterium smegmatis General Physics and Astronomy 610 Medicine & health 1600 General Chemistry Microbial Sensitivity Tests Bioinformatics Crystallography X-Ray Ribosome General Biochemistry Genetics and Molecular Biology Article Cell-free system Inhibitory Concentration 50 Mice 1300 General Biochemistry Genetics and Molecular Biology RNA Ribosomal 16S Sepsis medicine Escherichia coli Animals Humans Drug Interactions Multidisciplinary Base Sequence Cell-Free System Chemistry 10179 Institute of Medical Microbiology Aminoglycoside RNA General Chemistry Ribosomal RNA 3100 General Physics and Astronomy 3. Good health Anti-Bacterial Agents Cytosol Disease Models Animal Aminoglycosides Biochemistry Protein Biosynthesis 570 Life sciences biology Nucleic Acid Conformation Antibacterial activity Ribosomes |
| Zdroj: | Nature Communications Nature Communications, 5 'Nature Communications ', vol: 5, pages: 3112-1-3112-11 (2014) |
| ISSN: | 2041-1723 |
| Popis: | Clinical use of 2-deoxystreptamine aminoglycoside antibiotics, which target the bacterial ribosome, is compromised by adverse effects related to limited drug selectivity. Here we present a series of 4′,6′-O-acetal and 4′-O-ether modifications on glucopyranosyl ring I of aminoglycosides. Chemical modifications were guided by measuring interactions between the compounds synthesized and ribosomes harbouring single point mutations in the drug-binding site, resulting in aminoglycosides that interact poorly with the drug-binding pocket of eukaryotic mitochondrial or cytosolic ribosomes. Yet, these compounds largely retain their inhibitory activity for bacterial ribosomes and show antibacterial activity. Our data indicate that 4′-O-substituted aminoglycosides possess increased selectivity towards bacterial ribosomes and little activity for any of the human drug-binding pockets. Aminoglycoside antibiotics target the ribosome but their limited selectivity for the bacterial ribosome can cause side effects in humans. Here, the authors synthesize 4′-O-ether or 4′,6′-O-acetal modifications and show that these compounds possess increased selectivity against bacterial ribosomes. |
| Databáze: | OpenAIRE |
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