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Publication Abstract from PubMed

Many antibiotics inhibit bacterial growth by binding to the ribosome and interfering with protein biosynthesis. Macrolides represent one of the most successful classes of ribosome-targeting antibiotics. The main clinically relevant mechanism of resistance to macrolides is dimethylation of the 23S rRNA nucleotide A2058, located in the drug-binding site, a reaction catalyzed by Erm-type rRNA methyltransferases. Here, we present the crystal structure of the Erm-dimethylated 70S ribosome at 2.4 A resolution, together with the structures of unmethylated 70S ribosome functional complexes alone or in combination with macrolides. Altogether, our structural data do not support previous models and, instead, suggest a principally new explanation of how A2058 dimethylation confers resistance to macrolides. Moreover, high-resolution structures of two macrolide antibiotics bound to the unmodified ribosome reveal a previously unknown role of the desosamine moiety in drug binding, laying a foundation for the rational knowledge-based design of macrolides that can overcome Erm-mediated resistance.

Structure of Erm-modified 70S ribosome reveals the mechanism of macrolide resistance.,Svetlov MS, Syroegin EA, Aleksandrova EV, Atkinson GC, Gregory ST, Mankin AS, Polikanov YS Nat Chem Biol. 2021 Apr;17(4):412-420. doi: 10.1038/s41589-020-00715-0. Epub 2021 , Jan 18. PMID:33462493^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.