Structure of Erm-modified 70S ribosome reveals the mechanism of macrolide resistance.

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 the Erm-type rRNA-methyltransferases. Here, we present the crystal structure of the Erm-dimethylated 70S ribosome at 2.4Å resolution together with the structures of unmethylated 70S ribosome functional complexes alone and in combination with macrolides. Altogether, our structural data do not support the 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 revealed a previously unknown role of desosamine moiety in drug binding, laying a foundation for the rational knowledge-based design of macrolides that can overcome Erm-mediated resistance.