Structural modification of oxazolidinone antibiotics alters nascent peptide stalling preference and peptide trajectory through the ribosome.

Authors

Jordan I Kleinman, Tushar Raskar, Dorota Klepacki, Teresa Szal, Nora Vázquez-Laslop, Alexander S Mankin, James S Fraser, Danica Galonić Fujimori

Published in

bioRxiv : the preprint server for biology. Feb 18, 2026. Epub Feb 18, 2026.

Abstract

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 residues. Delpazolid, which shares the C5 hydroxymethyl moiety with tedizolid, shows a similar preference. Structural analysis of the ribosome with tedizolid and a stalled nascent peptide showed a compacted, helical conformation of the nascent chain induced by the drug. Our findings reveal that stalling preferences of oxazolidinones can be modulated by structural modifications within this antibiotic class.

PMID:
41757012
Bibliographic data and abstract were imported from PubMed on 09 Oct 2026.

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