Natural variation in the drug-binding residues of bacterial ribosomes

Drugs that target bacterial ribosomes are widely used in modern medicine and veterinary practice to treat bacterial infections and prevent the spread of antimicrobial resistance. However, most studies on targeting ribosomes with drugs are limited to just a few model organisms. Consequently, we do not know whether the ribosomal drug-binding sites observed in model bacteria are as highly conserved across bacteria as is currently implied. In this study, we address this question using a simple but powerful computational pipeline that filters out rare variants and sequencing errors to identify conserved changes at ribosomal drug-binding sites across the bacterial tree of life. This allows us to assess the conservation of 82 individual drug-binding residues of bacterial ribosomes from 8,809 bacterial species and trace their evolution throughout >4 billion years of bacterial history. Contrary to the common belief in the high conservation of ribosomal drug-binding residues, we find extensive variation among bacterial phyla and show that approximately 10% of species bear intrinsic ribosomal RNA (rRNA) substitutions that were previously observed only in clinical isolates of drug-resistant bacteria. Our work illustrates that our traditional use of Escherichia coli or other model bacteria to understand how bacterial ribosomes are targeted with drugs can be oversimplistic and misleading, as it overlooks widespread lineage-specific variation that make the drug-binding sites of some bacteria more dissimilar to E.coli than E.coli is to humans. These findings will have numerous implications for the lineage-specific use of ribosome-targeting antibiotics that are currently viewed as universal inhibitors of bacterial protein synthesis.