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

Bertrand Beckert, Elodie C. Leroy, Shanmugapriya Sothiselvam, Lars V. Bock (), Maxim S. Svetlov, Michael Graf, Stefan Arenz, Maha Abdelshahid, Britta Seip, Helmut Grubmüller, Alexander S. Mankin, C. Axel Innis (), Nora Vázquez-Laslop () and Daniel N. Wilson ()
Additional contact information
Bertrand Beckert: University of Hamburg
Elodie C. Leroy: Institut Européen de Chimie et Biologie
Shanmugapriya Sothiselvam: University of Illinois at Chicago
Lars V. Bock: Max Planck Institute for Biophysical Chemistry
Maxim S. Svetlov: University of Illinois at Chicago
Michael Graf: University of Hamburg
Stefan Arenz: University of Hamburg
Maha Abdelshahid: University of Hamburg
Britta Seip: Institut Européen de Chimie et Biologie
Helmut Grubmüller: Max Planck Institute for Biophysical Chemistry
Alexander S. Mankin: University of Illinois at Chicago
C. Axel Innis: Institut Européen de Chimie et Biologie
Nora Vázquez-Laslop: University of Illinois at Chicago
Daniel N. Wilson: University of Hamburg

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (4)

Downloads: (external link)
https://www.nature.com/articles/s41467-021-24674-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24674-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-24674-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().