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In erythromycin–resistant bacteria, the N6 position of A2058 in 23S rRNA is mono– or dimethylated by Erm family methyltransferases. This modification results in cross–resistance to macrolides, lincosamides and streptogramin B. Most inhibitors of Erm methyltransferases developed up–to–date target the cofactor–binding pocket, resulting in a lack of selectivity whereas inhibitors that bind the substrate–binding pocket demonstrate low in vitro activity. In this study, a molecular docking approach followed by biochemical screening was applied to search for inhibitors targeting both cofactor– and substrate–binding pockets of ErmC′ methyltransferase. Based on the results of the molecular docking–based virtual screening of the clean–leads subset of the ZINC database, 29 compounds were chosen for experimental verification. Among them inhibitor 28 (ZINC code 32747906), with an IC₅₀ of 100 μM, decreased the …