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

## TL;DR

This study uses cryo-EM to examine how resistant Staphylococcus aureus strains bind antibiotics, offering insights into improving drug effectiveness.

## Contribution

The study provides high-resolution structural insights into solithromycin binding in macrolide-resistant S. aureus ribosomes.

## Key findings

- Cryo-EM structures of solithromycin-bound ribosomes reveal drug interactions in resistant strains.
- Structural analysis shows solithromycin binds despite double methylation of A2058 in 23S rRNA.
- Optimizing ketolide–ribosome interactions could enhance efficacy against resistant S. aureus.

## Abstract

Macrolide resistance in Staphylococcus aureus is mediated by Erm-family methyltransferases, altering ribosomal drug binding. Using cryo-EM, we analyze solithromycin-bound ribosomes from resistant strains, revealing interactions that may enhance antibiotic efficacy.

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.