Structure of Erm-modified 70S ribosome reveals the mechanism of macrolide resistance

Maxim S Svetlov, Egor A Syroegin, Elena V Aleksandrova, Gemma C Atkinson, Steven T Gregory, Alexander S Mankin, Yury S Polikanov

Research output: Contribution to journalArticlepeer-review

25 Citations (SciVal)


Many antibiotics inhibit bacterial growth by binding to the ribosome and interfering with protein biosynthesis. Macrolides represent one of the most successful classes of ribosome-targeting antibiotics. The main clinically relevant mechanism of resistance to macrolides is dimethylation of the 23S rRNA nucleotide A2058, located in the drug-binding site, a reaction catalyzed by Erm-type rRNA methyltransferases. Here, we present the crystal structure of the Erm-dimethylated 70S ribosome at 2.4 Å resolution, together with the structures of unmethylated 70S ribosome functional complexes alone or in combination with macrolides. Altogether, our structural data do not support previous models and, instead, suggest a principally new explanation of how A2058 dimethylation confers resistance to macrolides. Moreover, high-resolution structures of two macrolide antibiotics bound to the unmodified ribosome reveal a previously unknown role of the desosamine moiety in drug binding, laying a foundation for the rational knowledge-based design of macrolides that can overcome Erm-mediated resistance.

Original languageEnglish
Pages (from-to)412-420
JournalNature Chemical Biology
Publication statusPublished - 2021
Externally publishedYes

Subject classification (UKÄ)

  • Biochemistry and Molecular Biology


  • Anti-Bacterial Agents/pharmacology
  • Drug Resistance, Bacterial/genetics
  • Macrolides/metabolism
  • Methylation
  • RNA, Ribosomal/genetics
  • RNA, Ribosomal, 23S/genetics
  • Ribosomes/genetics


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