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

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posted on 28.04.2021, 21:50 by MS Svetlov, EA Syroegin, EV Aleksandrova, GC Atkinson, ST Gregory, Alexander MankinAlexander Mankin, Yury PolikanovYury Polikanov
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. [Figure not available: see fulltext.]

Funding

Structural basis of Erm-mediated macrolide resistance

National Institute of Allergy and Infectious Diseases

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Exploiting antibiotics to understand the ribosome and translation

National Institute of General Medical Sciences

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Molecular mechanisms of action of ribosome-targeting antibiotics.

National Institute of General Medical Sciences

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History

Citation

Svetlov, M. S., Syroegin, E. A., Aleksandrova, E. V., Atkinson, G. C., Gregory, S. T., Mankin, A. S.Polikanov, Y. S. (2021). Structure of Erm-modified 70S ribosome reveals the mechanism of macrolide resistance. Nature Chemical Biology, 17(4), 412-420. https://doi.org/10.1038/s41589-020-00715-0

Publisher

Springer Science and Business Media LLC

Language

en

issn

1552-4450