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

Svetlov, Maxim S ; Syroegin, Egor A ; Aleksandrova, Elena V ; Atkinson, Gemma C LU ; Gregory, Steven T ; Mankin, Alexander S and Polikanov, Yury S (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
; ; ; ; ; and
publishing date
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}},
}