Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
Department of Microbiology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan.
J Med Chem. 2020 Sep 10;63(17):9803-9827. doi: 10.1021/acs.jmedchem.0c00973. Epub 2020 Aug 17.
The synthesis and biological evaluation of analogues of uridylpeptide antibiotics were described, and the molecular interaction between the 3'-hydroxy analogue of mureidomycin A (3'-hydroxymureidomycin A) and its target enzyme, phospho-MurNAc-pentapeptide transferase (MraY), was analyzed in detail. The structure-activity relationship (SAR) involving MraY inhibition suggests that the side chain at the urea-dipeptide moiety does not affect the MraY inhibition. However, the anti- activity is in great contrast and the urea-dipeptide motif is a key contributor. It is also suggested that the nucleoside peptide permease NppA1A2BCD is responsible for the transport of 3'-hydroxymureidomycin A into the cytoplasm. A systematic SAR analysis of the urea-dipeptide moiety of 3'-hydroxymureidomycin A was further conducted and the antibacterial activity was determined. This study provides a guide for the rational design of analogues based on uridylpeptide antibiotics.
本研究描述了尿嘧啶肽抗生素类似物的合成与生物评价，并详细分析了 mureidomycin A 的 3'-羟基类似物（3'-羟基 mureidomycin A）与靶酶磷酸-MurNAc-五肽转移酶（MraY）之间的分子相互作用。涉及 MraY 抑制的构效关系（SAR）表明，脲二肽部分的侧链不影响 MraY 抑制。然而，活性却大相径庭，脲二肽基序是一个关键贡献者。研究还表明核苷肽转运蛋白 NppA1A2BCD 负责将 3'-羟基 mureidomycin A 转运到细胞质中。进一步对 3'-羟基 mureidomycin A 的脲二肽部分进行了系统的 SAR 分析，并测定了其抗菌活性。该研究为基于尿嘧啶肽抗生素的类似物的合理设计提供了指导。
