School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China.
National Engineering Research Center for Strategic Drugs, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
Molecules. 2019 Jul 26;24(15):2719. doi: 10.3390/molecules24152719.
Polymyxins are considered to be the last-line antibiotics that are used to treat infections caused by multidrug-resistant (MDR) gram-negative bacteria; however, the plasmid-mediated transferable colistin resistance gene () has rendered polymyxins ineffective. Therefore, the protein encoded by , MCR-1, could be a target for structure-based design of inhibitors to tackle polymyxins resistance. Here, we identified racemic compound as a potential MCR-1 inhibitor by virtual screening, and 26 compound derivatives were synthesized and evaluated in vitro. In the cell-based assay, compound , , , , , , and displayed more potent activity than compound . Notably, 25 μΜ of compound or combined with 2 μg·mL-1 colistin could completely inhibit the growth of BL21(DE3) expressing , which exhibited the most potent activity. In the enzymatic assay, we elucidate that and could target the MCR-1 to inhibit the activity of the protein. Additionally, a molecular docking study showed that and could interact with Glu246 and Thr285 via hydrogen bonds and occupy well the cavity of the MCR-1 protein. These results may provide a potential avenue to overcome colistin resistance, and provide some valuable information for further investigation on MCR-1 inhibitors.
多黏菌素被认为是治疗多重耐药（MDR）革兰氏阴性菌感染的最后一线抗生素；然而，质粒介导的可转移黏菌素耐药基因（mcr-1）已使多黏菌素失去作用。因此，mcr-1 编码的蛋白 MCR-1 可能成为基于结构的抑制剂设计的靶点，以解决多黏菌素耐药性问题。在这里，我们通过虚拟筛选鉴定出外消旋化合物 作为潜在的 MCR-1 抑制剂，合成并评估了 26 种化合物 衍生物。在基于细胞的测定中，化合物 、 、 、 、 、 和 显示出比化合物 更强的活性。值得注意的是，25 μM 的化合物 或 与 2 μg·mL-1 黏菌素联合使用可完全抑制表达 mcr-1 的 BL21(DE3)的生长，其活性最强。在酶测定中，我们阐明 和 可以靶向 MCR-1 抑制蛋白的活性。此外，分子对接研究表明 和 可以通过氢键与 Glu246 和 Thr285 相互作用，并很好地占据 MCR-1 蛋白的腔。这些结果可能为克服黏菌素耐药性提供了一个潜在的途径，并为进一步研究 MCR-1 抑制剂提供了一些有价值的信息。
