Macrolide-ketolide inhibition of MLS-resistant ribosomes is improved by alternative drug interaction with domain II of 23S rRNA

Mol Microbiol. 2000 Apr;36(1):183-93. doi: 10.1046/j.1365-2958.2000.01841.x.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Base Sequence
  • Binding Sites
  • Clarithromycin / pharmacology
  • Drug Interactions
  • Drug Resistance, Microbial
  • Erythromycin / analogs & derivatives*
  • Escherichia coli / drug effects
  • Ketolides*
  • Macrolides*
  • Microbial Sensitivity Tests
  • Molecular Sequence Data
  • Mutation
  • Protein Synthesis Inhibitors / pharmacology*
  • RNA, Ribosomal, 23S / drug effects*
  • RNA, Ribosomal, 23S / genetics
  • Ribosomes / drug effects*
  • Ribosomes / genetics


  • Anti-Bacterial Agents
  • Ketolides
  • Macrolides
  • Protein Synthesis Inhibitors
  • RNA, Ribosomal, 23S
  • RU 56006
  • RU 64004
  • Erythromycin
  • Clarithromycin
  • telithromycin