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bioRxiv · 10.64898/2026.02.16.706219

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

Kleinman, J. I.·Raskar, T.·Klepacki, D.·Szal, T.·Vazquez-Laslop, N.·Mankin, A.·Fraser, J. S.·Fujimori, D. G.
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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.

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Kleinman, J. I., Raskar, T., Klepacki, D., Szal, T., Vazquez-Laslop, N., Mankin, A., Fraser, J. S., Fujimori, D. G.. 2026-02-18. Structural modification of oxazolidinone antibiotics alters nascent peptide stalling preference and peptide trajectory through the ribosome. https://doi.org/10.64898/2026.02.16.706219

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