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Novel inhibitors of the rRNA ErmC' methyltransferase to block resistance to macrolides, lincosamides, streptogramine B antibiotics
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2018-01-06 , DOI: 10.1016/j.ejmech.2017.11.032
Ilona P. Foik , Irina Tuszynska , Marcin Feder , Elzbieta Purta , Filip Stefaniak , Janusz M. Bujnicki

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 minimal inhibitory concentration of erythromycin in the Escherichia coli strain overexpressing ErmC'. Docking analysis of 28 to the ErmC′ structure and the competitive ligand binding assay revealed a non–competitive model of inhibition. Inhibitor 28 served as a template for similarity–based virtual screening, which resulted in the identification of two derivatives 3s (ZINC code 62022572) and 4s (ZINC code 49032257) with an IC50 of 116 μM and 110 μM, respectively. Our results provide a basis for the development of inhibitors against the Erm–family of enzymes.



中文翻译:

rRNA ErmC'甲基转移酶的新型抑制剂可阻断对大环内酯类,林可酰胺,链霉菌素B抗生素的耐药性

在抗红霉素的细菌中,23S rRNA中A2058的N6位置被Erm家族甲基转移酶单或二甲基化。这种修饰导致对大环内酯类,林可酰胺类和链霉菌素B的交叉耐药。大多数最新开发的Erm甲基转移酶抑制剂均靶向辅因子结合袋,导致缺乏选择性,而与底物结合袋结合的抑制剂显示出较低的选择性。体外活动。在这项研究中,分子对接方法随后进行了生化筛选,以寻找针对ErmC'甲基转移酶的辅因子和底物结合口袋的抑制剂。基于分子对接的ZINC数据库清洁铅子集虚拟筛选结果,选择了29种化合物进行实验验证。其中抑制剂28(锌代码32747906),与IC 50为100μM的,红霉素的最小抑菌浓度在减少大肠杆菌菌株过表达ERMC”。对28与ErmC'结构的对接分析和竞争性配体结合测定揭示了一种非竞争性抑制模型。抑制剂28用作基于相似性的虚拟筛选的模板,从而鉴定出IC 50分别为116μM和110μM的两个导数3s(ZINC代码62022572)和4s(ZINC代码49032257)。我们的结果为开发针对酶Erm家族的抑制剂提供了基础。

更新日期:2018-01-06
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