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Titolo:
Macrolide-ketolide inhibition of MLS-resistant ribosomes is improved by alternative drug interaction with domain II of 23S rRNA
Autore:
Douthwaite, S; Hansen, LH; Mauvais, P;
Indirizzi:
Odense Univ, Dept Mol Biol, DK-5230 Odense M, Denmark Odense Univ OdenseDenmark M v, Dept Mol Biol, DK-5230 Odense M, Denmark Hoechst Marion Roussel, Lab Bacterial Biochem, F-93235 Romainville, FranceHoechst Marion Roussel Romainville France F-93235 35 Romainville, France
Titolo Testata:
MOLECULAR MICROBIOLOGY
fascicolo: 1, volume: 36, anno: 2000,
pagine: 183 - 192
SICI:
0950-382X(200004)36:1<183:MIOMRI>2.0.ZU;2-5
Fonte:
ISI
Lingua:
ENG
Soggetto:
IN-VITRO ACTIVITY; C-13 NMR-SPECTRA; ERYTHROMYCIN RESISTANCE; ESCHERICHIA-COLI; HELICOBACTER-PYLORI; CLARITHROMYCIN RESISTANCE; POINT MUTATIONS; GENETIC-BASIS; RNA GENE; RU-64004;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
46
Recensione:
Indirizzi per estratti:
Indirizzo: Douthwaite, S Odense Univ, Dept Mol Biol, DK-5230 Odense M, Denmark OdenseUniv Odense Denmark M ol, DK-5230 Odense M, Denmark
Citazione:
S. Douthwaite et al., "Macrolide-ketolide inhibition of MLS-resistant ribosomes is improved by alternative drug interaction with domain II of 23S rRNA", MOL MICROB, 36(1), 2000, pp. 183-192

Abstract

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 ofthe cladinose, and substitution of a 3-keto group (forming the ketolide RU56006), results in loss of the A752 interaction and an approximate to 100-fold drop in drug binding affinity. Within domain V, the key determinant ofdrug binding is nucleotide A2058 and substitution of G at this position isthe 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 drug11/12 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 toachieve binding to the ribosomes of resistant pathogens in which the domain V interaction is perturbed.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 04/07/20 alle ore 17:33:02