Bacterial 50S ribosomal subunit 23S rRNA macrolide binding site (23S rRNA macrolide site)

The bacterial 50S ribosomal subunit 23S rRNA macrolide binding site is a critical pharmacological target located within the large subunit of the bacterial ribosome (Wilson, 2014). Specifically, macrolide antibiotics bind to the 23S rRNA at the entrance of the nascent peptide exit tunnel (NPET), near the peptidyl transferase center (PTC) (Vázquez-Laslop & Mankin, 2018). This binding physically obstructs the passage of the growing polypeptide chain, leading to the premature release of peptidyl-tRNA and the cessation of protein synthesis (StatPearls, 2023). Because this site is highly conserved across many bacterial species but differs significantly from eukaryotic ribosomes, it allows for selective toxicity against pathogens (Poehlsgaard & Douthwaite, 2005). It is the primary target for treating a wide range of respiratory, skin, and sexually transmitted infections caused by Gram-positive and some Gram-negative bacteria (NIH, 2022). Clinical efficacy is increasingly challenged by resistance mechanisms, such as the methylation of specific adenine residues (e.g., A2058) within the 23S rRNA by Erm methyltransferases or the presence of efflux pumps (Nature Reviews Microbiology, 2016). Understanding the structural nuances of this site has led to the development of newer generations of antibiotics, such as ketolides, which maintain activity against some resistant strains by forming additional contacts with the rRNA (Güleryüz et al., 2020). Overall, this site remains one of the most successful targets in antimicrobial chemotherapy due to its essential role in bacterial viability.

Other names

23S ribosomal RNA50S ribosomal subunitMacrolide-lincosamide-streptogramin B (MLSB) binding siteNascent peptide exit tunnel (NPET) binding site

Inhibition of bacterial protein synthesis by binding to the 23S rRNA and sterically blocking the nascent peptide exit tunnel, leading to premature dissociation of peptidyl-tRNA (Wilson, 2014; StatPearls, 2023).