Mechanisms of Context-Specific Action of Classic Ribosome-Targeting Antibiotics

The ribosome is a universal molecular machine that synthesizes all cellular proteins. Although eukaryotic and prokaryotic ribosomes serve the same purpose and share many structural features, the latter is sufficiently distinct to serve as a target for antibiotics. In recent years, growing evidence has reshaped our understanding of both the classical and modern ribosome-targeting drugs. Among these, chloramphenicol and macrolides are the most prominent examples. Since their discovery in the 40s-50s of the past century, these two classes of drugs have been considered inhibitors of every peptide bond formation regardless of the substrates bound to the ribosome. Recent studies revealed that, instead, they arrest translation only when the ribosome encounters a particular combination of P-site (peptidyl-tRNA) and A-site (aminoacyl-tRNA) substrates. This phenomenon was later termed context-specificity of drug action. How even the best studies of these selective ribosome inhibitors act at the molecular level is not understood: the structural details that underlie their context-specificity remain unknown. Our poor comprehension of how ribosome-targeting antibiotics work significantly hampers the ability to rationally develop potent new drugs to combat the growing number of resistant bacterial pathogens. The current work is dedicated to deciphering molecular mechanisms of context-specific action of two well-known and widely used classes of ribosome antibiotics – macrolides and phenicols.