Muraymycin Nucleoside Antibiotics: Structure-Activity Relationship for Variations in the Nucleoside Unit
Muraymycin Nucleoside Antibiotics: Structure-Activity Relationship for Variations in the Nucleoside Unit
复制标题
DOI：
10.3390/molecules25010022
复制
发表时间：
2020-01-01
期刊：
影响因子：
4.6
通讯作者：
Ducho, Christian
中科院分区：
文献类型：
--
作者：
Heib, Anna;Niro, Giuliana;Ducho, Christian
Muraymycins是天然核苷类抗生素的一个亚类，具有很好的抗菌活性。它们抑制细菌酶易位酶I（MraY），这是一种临床上尚未开发的介导细菌肽聚糖生物合成的重要细胞内步骤的靶标。已经合成了几种结构简化的村霉素类似物用于构效关系（SAR）研究。我们现在报道核苷单元具有前所未有的变化的新型衍生物。为了合成这些新的Muraymycin类似物，我们采用了一种促进不同的核苷基氨基酸基序的引入的二分方法。这也包括胸苷和5-氟尿苷衍生的核苷核心结构。使用MraY活性的体外测定，发现在嘧啶核碱基的5位引入取代基导致对MraY的抑制活性的显著损失。核碱基芳香性的丧失（通过尿嘧啶C5-C6双键的还原）导致约1000个碱基。抑制效力降低十倍。相比之下，去除2 '-羟基提供保留的活性，因此证明核糖部分的修饰可能是良好耐受的。总的来说，这些新的SAR见解将指导未来设计新型村霉素类似物，以实现其潜在的抗菌药物候选物的发展。
Muraymycins are a subclass of naturally occurring nucleoside antibiotics with promising antibacterial activity. They inhibit the bacterial enzyme translocase I (MraY), a clinically yet unexploited target mediating an essential intracellular step of bacterial peptidoglycan biosynthesis. Several structurally simplified muraymycin analogues have already been synthesized for structure-activity relationship (SAR) studies. We now report on novel derivatives with unprecedented variations in the nucleoside unit. For the synthesis of these new muraymycin analogues, we employed a bipartite approach facilitating the introduction of different nucleosyl amino acid motifs. This also included thymidine- and 5-fluorouridine-derived nucleoside core structures. Using an in vitro assay for MraY activity, it was found that the introduction of substituents in the 5-position of the pyrimidine nucleobase led to a significant loss of inhibitory activity towards MraY. The loss of nucleobase aromaticity (by reduction of the uracil C5-C6 double bond) resulted in a ca. tenfold decrease in inhibitory potency. In contrast, removal of the 2'-hydroxy group furnished retained activity, thus demonstrating that modifications of the ribose moiety might be well-tolerated. Overall, these new SAR insights will guide the future design of novel muraymycin analogues for their potential development towards antibacterial drug candidates.