Structural and mechanistic basis for translation inhibition by macrolide and ketolide antibiotics

2021 | journal article; research paper. A publication with affiliation to the University of Göttingen.

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​Structural and mechanistic basis for translation inhibition by macrolide and ketolide antibiotics​
Beckert, B.; Leroy, E. C.; Sothiselvam, S.; Bock, L. V. ; Svetlov, M. S.; Graf, M. & Arenz, S. et al.​ (2021) 
Nature Communications12(1) pp. 4466​.​ DOI: https://doi.org/10.1038/s41467-021-24674-9 

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Authors
Beckert, Bertrand; Leroy, Elodie C.; Sothiselvam, Shanmugapriya; Bock, Lars V. ; Svetlov, Maxim S.; Graf, Michael; Arenz, Stefan; Abdelshahid, Maha; Seip, Britta; Grubmüller, Helmut ; Mankin, Alexander S.; Innis, C. Axel; Vázquez-Laslop, Nora; Wilson, Daniel N.
Abstract
Macrolides and ketolides comprise a family of clinically important antibiotics that inhibit protein synthesis by binding within the exit tunnel of the bacterial ribosome. While these antibiotics are known to interrupt translation at specific sequence motifs, with ketolides predominantly stalling at Arg/Lys-X-Arg/Lys motifs and macrolides displaying a broader specificity, a structural basis for their context-specific action has been lacking. Here, we present structures of ribosomes arrested during the synthesis of an Arg-Leu-Arg sequence by the macrolide erythromycin (ERY) and the ketolide telithromycin (TEL). Together with deep mutagenesis and molecular dynamics simulations, the structures reveal how ERY and TEL interplay with the Arg-Leu-Arg motif to induce translational arrest and illuminate the basis for the less stringent sequence-specific action of ERY over TEL. Because programmed stalling at the Arg/Lys-X-Arg/Lys motifs is used to activate expression of antibiotic resistance genes, our study also provides important insights for future development of improved macrolide antibiotics.
Issue Date
2021
Journal
Nature Communications 
Project
EXC 2067: Multiscale Bioimaging 
Organization
Max-Planck-Institut für biophysikalische Chemie 
Working Group
RG Grubmüller 
ISSN
2041-1723
Language
English

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