Effect of ribosomal protein mutation on macrolide binding affinity in Staphylococcus aureus: A molecular docking study

Staphylococcus aureus (S. aureus) is a common human pathogen that can cause a wide range of infections, from mild skin infections to severe complications, particularly in individuals with combat-related injuries. The pathogen's virulence, immune evasion mechanisms, and antibiotic resistance present significant challenges for clinical management and infection control. Resistance to macrolides is primarily associated with mechanisms that reduce the ability of these antibiotics to bind to their targets. The aim of the study was to investigate the effect of mutations in bacterial ribosomal proteins on the binding affinity of macrolides through a molecular docking approach. Molecular docking was performed using AutoDock Vina (v1.2.5) software tool. The 3D structures of bacterial ribosomal proteins were retrieved from the Protein Data Bank (PDB) (PDB IDs: 4WCE and 6WRU) (https://www.rcsb.org/). Macrolide structures, such as erythromycin B, erythromycin C, and oleandomycin, were downloaded from PubChem (https://pubchem.ncbi.nlm.nih.gov/). Selected macrolides were docked into the L6, L22, and L23 proteins of the 50S ribosomal subunit from S. aureus. Visualization of docking results was performed in PyMOL and Discovery Studio 2024 Client. The docking analysis demonstrated that the studied macrolides interact with target proteins through van der Waals forces, hydrogen bonds, carbon–hydrogen bonds, and hydrophobic contacts, with binding energies ranging from –6.1 to –8.2 kcal/mol. Erythromycin C exhibited the highest binding affinity (–8.2 kcal/mol) toward the unmutated L23 protein, predominantly via van der Waals and hydrophobic interactions (Lys77, Val11, Arg9). The Ile87Asp substitution in the C-terminal loop of L23 altered the conformation of the 50S ribosomal subunit’s peptide exit tunnel, reducing erythromycin C affinity to –6.6 kcal/mol. Consistent reductions in binding affinity were also observed for mutated L6 and L22 proteins, regardless of the docked macrolide. Although this study is based on molecular docking, the results suggest that amino acid residues in the peptide exit tunnel of unmutated ribosomal proteins interact with macrolides with high predicted binding affinity. Mutations associated with resistance are characterized by increased binding energy scores, indicating weaker predicted interactions. These findings highlight the potential value of further investigating ribosomal protein mutations as a pathway to understanding and potentially overcoming macrolide resistance.