N6', N6''', and O4' Modifications to Neomycin Affect Ribosomal Selectivity without Compromising Antibacterial Activity.
N6', N6''', and O4' Modifications to Neomycin Affect Ribosomal Selectivity without Compromising Antibacterial Activity.
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新霉素的 N6、N6 和 O4 修饰会影响核糖体选择性，但不会影响抗菌活性。
DOI：
10.1021/acsinfecdis.6b00214
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发表时间：
2017
影响因子：
5.3
通讯作者：
Crich,David
中科院分区：
文献类型：
--
作者：
Sati,GirishC;Shcherbakov,Dimitri;Hobbie,SvenN;Vasella,Andrea;Böttger,ErikC;Crich,David
本文报道了一系列在N6′和/或N6 ′上带有2-羟乙基取代基的新霉素衍生物的合成。通过与野生型细菌核糖体及其与真核生物解码A位点的杂交体的无细胞翻译测定，我们研究了单个取代基及其组合如何影响目标水平的活性和选择性。原则上，如无细胞翻译试验所示，N6′和N6 ′端位置的修饰可以增强靶标选择性，而不影响抗菌活性。与6′OH氨基糖苷巴龙霉素一样，4′-O-乙基修饰影响新霉素及其6′-N-（2-羟乙基）衍生物的核糖体活性、选择性和抗菌特性。修饰的氨基糖苷类对革兰氏阳性和革兰氏阴性菌模型表现出良好的抗菌活性，包括ESKAPE病原体金黄色葡萄球菌、肺炎克雷伯菌、阴沟肠杆菌和鲍曼不动杆菌。
The synthesis of a series of neomycin derivatives carrying the 2-hydroxyethyl substituent on N6′ and/or N6‴ both alone and in combination with a 4′-O-ethyl group is described. By means of cell-free translation assays with wild-type bacterial ribosomes and their hybrids with eukaryotic decoding A sites, we investigate how individual substituents and their combinations affect activity and selectivity at the target level. In principle, and as shown by cell-free translation assays, modifications of the N6′ and N6‴ positions allow enhancement of target selectivity without compromising antibacterial activity. As with the 6′OH aminoglycoside paromomycin, the 4′-O-ethyl modification affects the ribosomal activity, selectivity, and antibacterial profile of neomycin and its 6′-N-(2-hydroxyethyl) derivatives. The modified aminoglycosides show good antibacterial activity against model Gram-positive and Gram-negative microbes including the ESKAPE pathogensStaphylococcus aureus,Klebsiella pneumoniae,Enterobacter cloacae, andAcinetobacter baumannii.