Structure-activity exploration of a small-molecule Lipid II inhibitor.
Structure-activity exploration of a small-molecule Lipid II inhibitor.
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DOI：
10.2147/dddt.s79504
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
de Leeuw E
中科院分区：
文献类型：
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作者：
Fletcher S;Yu W;Huang J;Kwasny SM;Chauhan J;Opperman TJ;MacKerell AD Jr;de Leeuw E
我们最近发现了一些低分子量化合物，它们可以作为脂质 II 的抑制剂，脂质 II 是细菌细胞壁生物合成的重要前体。脂质 II 包含特殊脂质（细菌烯醇），该脂质通过焦磷酸盐与由肽聚糖亚基（N-乙酰葡糖胺 [GlcNAc]-N-乙酰胞壁酸 [MurNAc] 二糖与短五肽部分偶联）组成的亲水性头部基团相连。我们的先导化合物之一是二苯基三甲基吲哚啉鎓，称为 BAS00127538，它与脂质 II 的 MurNAc 部分和异戊二烯基尾部相互作用。在这里，我们报告了通过计算机分析和从头化学合成获得的 BAS00127538 衍生物的结构-活性关系。我们的结果表明，脂质 II 结合和细菌杀灭与三个特征有关：二苯基部分、吲哚基部分和吡喃鎓的正电荷。用 N-甲基吡啶鎓取代吡喃鎓部分（这可能对分子的稳定性很重要）不会改变脂质 II 结合或抗菌效力。
We have recently identified low-molecular weight compounds that act as inhibitors of Lipid II, an essential precursor of bacterial cell wall biosynthesis. Lipid II comprises specialized lipid (bactoprenol) linked to a hydrophilic head group consisting of a peptidoglycan subunit (N-acetyl glucosamine [GlcNAc]–N-acetyl muramic acid [MurNAc] disaccharide coupled to a short pentapeptide moiety) via a pyrophosphate. One of our lead compounds, a diphenyl-trimethyl indolene pyrylium, termed BAS00127538, interacts with the MurNAc moiety and the isoprenyl tail of Lipid II. Here, we report on the structure–activity relationship of BAS00127538 derivatives obtained by in silico analyses and de novo chemical synthesis. Our results indicate that Lipid II binding and bacterial killing are related to three features: the diphenyl moiety, the indolene moiety, and the positive charge of the pyrylium. Replacement of the pyrylium moiety with an N-methyl pyridinium, which may have importance in stability of the molecule, did not alter Lipid II binding or antibacterial potency.