Structure of Erm-modified 70S ribosome reveals the mechanism of macrolide resistance
(2021) In Nature Chemical Biology 17. p.412-420- Abstract
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... (More)
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.
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- author
- Svetlov, Maxim S ; Syroegin, Egor A ; Aleksandrova, Elena V ; Atkinson, Gemma C LU ; Gregory, Steven T ; Mankin, Alexander S and Polikanov, Yury S
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Anti-Bacterial Agents/pharmacology, Drug Resistance, Bacterial/genetics, Macrolides/metabolism, Methylation, RNA, Ribosomal/genetics, RNA, Ribosomal, 23S/genetics, Ribosomes/genetics
- in
- Nature Chemical Biology
- volume
- 17
- pages
- 412 - 420
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:33462493
- scopus:85100077228
- ISSN
- 1552-4469
- DOI
- 10.1038/s41589-020-00715-0
- language
- English
- LU publication?
- no
- id
- 67848fc7-416a-4f21-83c7-954dd4853764
- date added to LUP
- 2021-09-27 15:50:04
- date last changed
- 2024-06-30 20:26:29
@article{67848fc7-416a-4f21-83c7-954dd4853764, abstract = {{<p>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.</p>}}, author = {{Svetlov, Maxim S and Syroegin, Egor A and Aleksandrova, Elena V and Atkinson, Gemma C and Gregory, Steven T and Mankin, Alexander S and Polikanov, Yury S}}, issn = {{1552-4469}}, keywords = {{Anti-Bacterial Agents/pharmacology; Drug Resistance, Bacterial/genetics; Macrolides/metabolism; Methylation; RNA, Ribosomal/genetics; RNA, Ribosomal, 23S/genetics; Ribosomes/genetics}}, language = {{eng}}, pages = {{412--420}}, publisher = {{Nature Publishing Group}}, series = {{Nature Chemical Biology}}, title = {{Structure of Erm-modified 70S ribosome reveals the mechanism of macrolide resistance}}, url = {{http://dx.doi.org/10.1038/s41589-020-00715-0}}, doi = {{10.1038/s41589-020-00715-0}}, volume = {{17}}, year = {{2021}}, }