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Macrolide–ketolide inhibition of MLS‐resistant ribosomes is improved by alternative drug interaction with domain II of 23S rRNA
Author(s) -
Douthwaite Stephen,
Hansen Lykke Haastrup,
Mauvais Pascale
Publication year - 2000
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1046/j.1365-2958.2000.01841.x
Subject(s) - ketolide , biology , ribosome , 23s ribosomal rna , binding site , stereochemistry , biochemistry , antibacterial agent , antibiotics , rna , chemistry , gene
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 ≈ 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.