Our ability to use ribosome-targeting antibiotics against bacterial pathogens without affecting human ribosomes often relies on small differences in rRNA sequences between bacterial and eukaryotic species. For example, eukaryotic ribosomes tolerate aminoglycosides like neomycin (which inhibit bacterial ribosomes) due to substitutions in rRNA bases at the direct chemical interface between the ribosome and the drug: in humans, ribosomes carry G1408 and A1491, compared to A1408 and G1491 in bacteria like E. coli. These differences do not allow neomycin and similar drugs to occupy the drug-binding pocket, rendering eukaryotic ribosomes intrinsically drug resistant. Furthermore, introducing human-specific rRNA variants (G1408 or A1491) into bacterial ribosomes render bacterial ribosomes resistant to aminoglycosides, while conversely, introducing bacterial-type variants (A1408 or G1491) into yeast ribosomes confer sensitivity to these antibiotics. Thus, just a few rRNA base substitutions may enable selective targeting of bacterial ribosomes by over ten families of antibiotics while sparing eukaryotic ribosomes, leading to many implications for clinical practice, research, and agriculture.
However, emerging evidence shows that many bacterial lineages differ not only from humans but also from each other—just as many eukaryotes differ from humans,—exhibiting divergent and species-specific sequences in ribosomal drug-binding residues. This finding is particularly important because—in organisms where these differences have been assessed experimentally—these sequence variation typically confer intrinsic resistance to ribosome-targeting drugs.
Here, we summarize current knowledge on the natural variation in ribosomal drug-binding sites across bacterial species (based on Ekemezie et al., 2025).