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Updated: Jun 14, 2025
A Tandem Liquid Chromatography–Mass Spectrometry-based Approach for Metabolite Analysis of Staphylococcus aureus
Published on: March 28, 2017
Structural studies on ribosomes of differentially macrolide-resistant Staphylococcus aureus strains
André Rivalta1, Aliza Fedorenko1, Alexandre Le Scornet2
1Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel.
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 microscopy, 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.
Insights
Antimicrobial resistance in Staphylococcus aureus is a growing threat. This study reveals how solithromycin binds to resistant bacterial ribosomes, offering insights for developing new antibiotics against drug-resistant infections.
Area of Science:
- Microbiology
- Structural Biology
- Drug Discovery
Background:
- Antimicrobial resistance (AMR) is a significant global health concern.
- Macrolide antibiotics are losing efficacy against pathogens like Staphylococcus aureus.
- Erm-family methyltransferases cause macrolide resistance by modifying 23S ribosomal RNA.
Purpose of the Study:
- To investigate the structural basis of macrolide-ribosome interactions in Staphylococcus aureus.
- To understand how ErmB-mediated methylation affects drug binding.
- To explore strategies for overcoming macrolide resistance in S. aureus.
Main Methods:
- Cryo-electron microscopy (cryo-EM) to determine high-resolution ribosome structures.
- Analysis of S. aureus strains with varying ermB expression.
- Microbiological and biochemical assays to validate drug binding and resistance.
Main Results:
- High-resolution structures of solithromycin-bound ribosomes, including those with A2058 dimethylation, were determined.
- Specific interactions enabling solithromycin binding despite resistance mechanisms were identified.
- Structural findings were corroborated by microbiological and biochemical data.
Conclusions:
- Solithromycin can bind to resistant S. aureus ribosomes, even with A2058 dimethylation.
- Understanding these interactions can guide the development of novel ketolides.
- Further optimization of ketolide-ribosome interactions may enhance efficacy against resistant S. aureus.
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