Kwak Seung-Hwa, Lim Won Young, Hao Aili, Mashalidis Ellene H, Kwon Do-Yeon, Jeong Pyeonghwa, Kim Mi Jung, Lee Seok-Yong, Hong Jiyong
Department of Chemistry, Duke University, Durham, NC, 27708, United States.
Department of Biochemistry, Duke University Medical Center, Durham, NC, 27710, United States.
Eur J Med Chem. 2021 Apr 5;215:113272. doi: 10.1016/j.ejmech.2021.113272. Epub 2021 Feb 6.
Antibiotic resistance is one of the most challenging global health issues and presents an urgent need for the development of new antibiotics. In this regard, phospho-MurNAc-pentapeptide translocase (MraY), an essential enzyme in the early stages of peptidoglycan biosynthesis, has emerged as a promising new antibiotic target. We recently reported the crystal structures of MraY in complex with representative members of naturally occurring nucleoside antibiotics, including muraymycin D2. However, these nucleoside antibiotics are synthetically challenging targets, which limits the scope of medicinal chemistry efforts on this class of compounds. To gain access to active muraymycin analogs with reduced structural complexity and improved synthetic tractability, we prepared and evaluated cyclopentane-based muraymycin analogs for targeting MraY. For the installation of the 1,2-syn-amino alcohol group of analogs, the diastereoselective isocyanoacetate aldol reaction was explored. The structure-activity relationship analysis of the synthesized analogs suggested that a lipophilic side chain is essential for MraY inhibition. Importantly, the analog 20 (JH-MR-23) showed antibacterial efficacy against Staphylococcus aureus. These findings provide insights into designing new muraymycin-based MraY inhibitors with improved chemical tractability.
抗生素耐药性是全球最具挑战性的健康问题之一，迫切需要开发新的抗生素。在这方面，磷酸化胞壁酰五肽转运酶（MraY）是肽聚糖生物合成早期阶段的一种必需酶，已成为一个有前景的新抗生素靶点。我们最近报道了MraY与天然核苷类抗生素（包括muraymycin D2）的代表性成员形成复合物的晶体结构。然而，这些核苷类抗生素是合成上具有挑战性的靶点，这限制了针对这类化合物的药物化学研究范围。为了获得结构复杂性降低且合成可操作性提高的活性muraymycin类似物，我们制备并评估了用于靶向MraY的环戊烷类muraymycin类似物。为了引入类似物的1,2-顺式氨基醇基团，我们探索了非对映选择性异氰基乙酸酯羟醛反应。对合成类似物的构效关系分析表明，亲脂性侧链对于抑制MraY至关重要。重要的是，类似物20（JH-MR-23）对金黄色葡萄球菌显示出抗菌效果。这些发现为设计具有更好化学可操作性的新型基于muraymycin的MraY抑制剂提供了见解。
