Structural studies on ribosomes of differentially macrolide-resistant Staphylococcus aureus strains

André Rivalta; Aliza Fedorenko; Alexandre Le Scornet; Sophie Thompson; Yehuda Halfon; Elinor Breiner Goldstein; Sude Çavdaroglu; Tal Melenitzky; Disha Gajanan Hiregange; Ella Zimmerman; Anat Bashan; Mee Ngan Frances Yap; Ada Yonath

doi:10.26508/lsa.202503325

Structural studies on ribosomes of differentially macrolide-resistant Staphylococcus aureus strains

André Rivalta, Aliza Fedorenko, Alexandre Le Scornet, Sophie Thompson, Yehuda Halfon, Elinor Breiner Goldstein, Sude Çavdaroglu, Tal Melenitzky, Disha Gajanan Hiregange, Ella Zimmerman, Anat Bashan, Mee Ngan Frances Yap, Ada Yonath^*

^*Corresponding author for this work

Department of Chemical and Structural Biology

Research output: Contribution to journal › Article › peer-review

Abstract

Antimicrobial resistance is a major global health challenge, diminishing the efficacy of many antibiotics, including macrolides. In Staphylococcus aureus, an opportunistic pathogen, macrolide resistance is primarily mediated by Erm-family methyltransferases, which mono-or dimethylate A2058 in the 23S ribosomal RNA, reducing drug binding. Although macrolide–ribosome interactions have been characterized in nonpathogenic species, their structural basis in clinically relevant pathogens remains limited. In this study, we investigate the impact of ermB-mediated resistance on drug binding by analyzing ribosomes from S. aureus strains with varying levels of ermB expression and activity. Using cryo-electron micros-copy, we determined the high-resolution structures of solithromycin-bound ribosomes, including those with dimethylated A2058. Our structural analysis reveals the specific interactions that enable solithromycin binding despite double methylation and resistance, as corroborated by microbiological and biochemical data, suggesting that further optimization of ketolide–ribosome interactions could enhance macrolide efficacy against resistant S. aureus strains.

Original language	English
Article number	e202503325
Number of pages	11
Journal	Life Science Alliance
Volume	8
Issue number	8
Early online date	9 Jun 2025
DOIs	https://doi.org/10.26508/lsa.202503325
Publication status	Published - Aug 2025

Funding

We thank the members of the A Yonath (in particular, Moshe Peretz and Shoshana Tel-Or) and M-NF Yap groups, as well as Nadav Elad from the Weizmann Electron Microscopy Unit and Yoav Barak from the BioNano Unit, for their interest and experimental support. This work was supported by the Kimmelman Center for Macromolecular Assemblies. A Yonath holds the Martin S and Helen Kimmel Professorial Chair at the Weizmann Institute of Science. The studies performed in the USA were supported by the National Institutes of Health R01AI150986 (to M-NF Yap) and in part by the Department of Defense W81XWH-18-1-0122 (to M-NF Yap).

All Science Journal Classification (ASJC) codes

Ecology
Biochemistry, Genetics and Molecular Biology (miscellaneous)
Plant Science
Health, Toxicology and Mutagenesis

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10.26508/lsa.202503325Licence: CC BY

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Rivalta, A., Fedorenko, A., Scornet, A. L., Thompson, S., Halfon, Y., Goldstein, E. B., Çavdaroglu, S., Melenitzky, T., Hiregange, D. G., Zimmerman, E., Bashan, A., Yap, M. N. F., & Yonath, A. (2025). Structural studies on ribosomes of differentially macrolide-resistant Staphylococcus aureus strains. Life Science Alliance, 8(8), Article e202503325. https://doi.org/10.26508/lsa.202503325

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abstract = "Antimicrobial resistance is a major global health challenge, diminishing the efficacy of many antibiotics, including macrolides. In Staphylococcus aureus, an opportunistic pathogen, macrolide resistance is primarily mediated by Erm-family methyltransferases, which mono-or dimethylate A2058 in the 23S ribosomal RNA, reducing drug binding. Although macrolide–ribosome interactions have been characterized in nonpathogenic species, their structural basis in clinically relevant pathogens remains limited. In this study, we investigate the impact of ermB-mediated resistance on drug binding by analyzing ribosomes from S. aureus strains with varying levels of ermB expression and activity. Using cryo-electron micros-copy, we determined the high-resolution structures of solithromycin-bound ribosomes, including those with dimethylated A2058. Our structural analysis reveals the specific interactions that enable solithromycin binding despite double methylation and resistance, as corroborated by microbiological and biochemical data, suggesting that further optimization of ketolide–ribosome interactions could enhance macrolide efficacy against resistant S. aureus strains.",

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AU - Rivalta, André

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AU - Thompson, Sophie

AU - Halfon, Yehuda

AU - Goldstein, Elinor Breiner

AU - Çavdaroglu, Sude

AU - Melenitzky, Tal

AU - Hiregange, Disha Gajanan

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AU - Yonath, Ada

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AB - Antimicrobial resistance is a major global health challenge, diminishing the efficacy of many antibiotics, including macrolides. In Staphylococcus aureus, an opportunistic pathogen, macrolide resistance is primarily mediated by Erm-family methyltransferases, which mono-or dimethylate A2058 in the 23S ribosomal RNA, reducing drug binding. Although macrolide–ribosome interactions have been characterized in nonpathogenic species, their structural basis in clinically relevant pathogens remains limited. In this study, we investigate the impact of ermB-mediated resistance on drug binding by analyzing ribosomes from S. aureus strains with varying levels of ermB expression and activity. Using cryo-electron micros-copy, we determined the high-resolution structures of solithromycin-bound ribosomes, including those with dimethylated A2058. Our structural analysis reveals the specific interactions that enable solithromycin binding despite double methylation and resistance, as corroborated by microbiological and biochemical data, suggesting that further optimization of ketolide–ribosome interactions could enhance macrolide efficacy against resistant S. aureus strains.

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Structural studies on ribosomes of differentially macrolide-resistant Staphylococcus aureus strains

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