UCSF

The oxazolidinone antibiotic linezolid binds to the peptidyl transferase center of the ribosome, where it inhibits a subset of peptide bond formation events. This context-specificity of translation inhibition is dictated by the nature of the amino acid at the penultimate position of the nascent peptide. It remains unknown whether this is a general feature of oxazolidinones and whether it can be modulated by their structural alterations. Here, we show that the oxazolidinone tedizolid also inhibits translation in a context-specific manner, but with dramatically altered selectivity, favoring Ile, His, and Gln as the penultimate (-1) residues. Delpazolid, which shares the C5-hydroxymethyl moiety with tedizolid, shows a similar preference. Structural analysis of ribosomes stalled by tedizolid or delpazolid revealed differences in nascent peptide conformation as a function of the penultimate amino acid, with Ile(-1) peptide adopting a compacted, helical conformation induced by the drug, while His(-1) peptides favored a more extended conformation, facilitated by extensive interactions of the imidazole moiety with both rRNA and the oxazolidinone ligand. Our findings reveal that stalling preferences of oxazolidinones can be modulated by structural modifications of antibiotic scaffold and conformational malleability of the nascent chain.