Macrolide-ketolide inhibition of MLS-resistant ribosomes is improved by alternative drug interaction with domain II of 23S rRNA
| Autor: | Pascale Mauvais, Stephen Douthwaite, Lykke Haastrup Hansen |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Ketolides
Molecular Sequence Data Microbial Sensitivity Tests Drug resistance Biology Microbiology Ribosome chemistry.chemical_compound 23S ribosomal RNA Clarithromycin Escherichia coli medicine Drug Interactions Nucleotide Binding site Molecular Biology Ketolide Cladinose Protein Synthesis Inhibitors chemistry.chemical_classification Binding Sites Base Sequence Drug Resistance Microbial Drug interaction Anti-Bacterial Agents Erythromycin RNA Ribosomal 23S chemistry Biochemistry Mutation Macrolides Ribosomes medicine.drug |
| Zdroj: | Douthwaite, S, Hansen, L H & Mauvais, P 2000, ' Macrolide-ketolide inhibition of MLS-resistant ribosomes is improved by alternative drug interaction with domain II of 23S rRNA ', Molecular Microbiology, vol. 36, no. 1, pp. 183-193 . https://doi.org/10.1046/j.1365-2958.2000.01841.x |
| ISSN: | 1365-2958 0950-382X |
| DOI: | 10.1046/j.1365-2958.2000.01841.x |
| Popis: | Udgivelsesdato: 2000-Apr The macrolide antibiotic erythromycin and its 6-O-methyl derivative (clarithromycin) bind to bacterial ribosomes primarily through interactions with nucleotides in domains II and V of 23S rRNA. The domain II interaction occurs between nucleotide A752 and the macrolide 3-cladinose moiety. Removal of the cladinose, and substitution of a 3-keto group (forming the ketolide RU 56006), results in loss of the A752 interaction and an approximately 100-fold drop in drug binding affinity. Within domain V, the key determinant of drug binding is nucleotide A2058 and substitution of G at this position is the major cause of drug resistance in some clinical pathogens. The 2058G mutation disrupts the drug-domain V contact and leads to a further > 25 000-fold decrease in the binding of RU 56006. Drug binding to resistant ribosomes can be improved over 3000-fold by forming an alternative and more effective contact to A752 via alkyl-aryl groups linked to a carbamate at the drug 11/12 position (in the ketolide antibiotics HMR 3647 and HMR 3004). The data indicate that simultaneous drug interactions with domains II and V strengthen binding and that the domain II contact is of particular importance to achieve binding to the ribosomes of resistant pathogens in which the domain V interaction is perturbed. |
| Databáze: | OpenAIRE |
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