Evolutionary divergence of drug-binding sites in ribosomes

Abstract

Ribosome-targeting drugs are widely used in medicine, research, and agriculture. However, most of our knowledge about how these drugs work comes from studying a few model organisms—such as Escherichia coli and Thermus thermophilus (for bacteria), and yeast and humans (for eukaryotes). As a result, it is often assumed that drug-binding sites are the same across all organisms. However, emerging evidence suggests otherwise. We aimed to understand how drug-binding sites in ribosomes vary across different organisms and how many organisms in nature bear rRNA substitutions in the drug-binding sites of their ribosomes. To answer this, we developed a novel approach to address issues such as data bias, sequencing errors, pseudogenes, and chimeric sequences. Using this method, we systematically analysed drugbinding sites in eukaryotic ribosomes and identified lineages bearing rRNA substitutions in the drug-binding sites of their ribosomes compared to humans and yeast. We then extended our analysis to bacterial species, comparing the conservation of the drug-binding sites of their ribosomes to that of the common model bacterium E. coli. Our findings suggest that the diversification of ribosomal drug-binding sites in bacteria began long before separation of the some of the earliest bacterial phyla, indicating that these variations are ancient. By using Streptomyces ribosomes—which have a modified drug-binding site—as a model, we explored how natural rRNA substitutions affect the orthosomycin family of drugs. Our analysis showed that while some substitutions may change how drug binds to the ribosome, others have little or no effect. Overall, this study offers a detailed understanding of how rRNA changes in the drugbinding site influence drug interactions. This knowledge can guide the precise use of these drugs and support the development of drugs targeting specific organisms.