How macrolide and ketolide antibiotics inhibit translation

Beckert, B., Leroy, E.C., Sothiselvam, S., Bock, L.V., Svetlov, M.S., Graf, M., Arenz, S., Abdelshahid, M., Seip, B., Grubmüller, H., Mankin, A.S., Innis, C.A., Vázquez-Laslop, N., Wilson, D.N. (2021) Structural and mechanistic basis for translation inhibition by macrolide and ketolide antibiotics. Nat Commun 12, 4466.

PDB entries: 7NSO, 7NSP, 7NSQ

EMDB entries: EMD-12573,  EMD-12574, EMD-12575

In this collaborative study with the Wilson, Mankin/Vázques-Laslop and Grubmüller labs, we use iTP-seq, biochemistry, cryo-EM and molecular simulations to determine the mechanism by which macrolides and ketolides, a large class of clinically important antibiotics, inhibit translation at +X+ motifs. In addition, we show that the antibiotics erythromycin (a macrolide) and telithromycin (a ketolide) stall ribosomes translating ermDL, the leader sequence responsible for induction of the ErmD resistance methyltransferase, via distinct mechanisms.