Sati Girish C, Shcherbakov Dimitri, Hobbie Sven N, Vasella Andrea, Böttger Erik C, Crich David
Department of Chemistry, Wayne State University , Detroit, Michigan 48202, United States.
Institute of Medical Microbiology, University of Zurich , 8006 Zurich, Switzerland.
ACS Infect Dis. 2017 May 12;3(5):368-377. doi: 10.1021/acsinfecdis.6b00214. Epub 2017 Apr 6.
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 pathogens Staphylococcus aureus, Klebsiella pneumoniae, Enterobacter cloacae, and Acinetobacter baumannii.
本文描述了一系列在N6'和/或N6‴上带有2-羟乙基取代基的新霉素衍生物的合成，这些取代基单独存在或与4'-O-乙基组合存在。通过使用野生型细菌核糖体及其与真核解码A位点的杂交体进行无细胞翻译测定，我们研究了各个取代基及其组合如何在靶标水平上影响活性和选择性。原则上，如无细胞翻译测定所示，N6'和N6‴位置的修饰可在不影响抗菌活性的情况下提高靶标选择性。与6'-OH氨基糖苷类巴龙霉素一样，4'-O-乙基修饰会影响新霉素及其6'-N-(2-羟乙基)衍生物的核糖体活性、选择性和抗菌谱。修饰后的氨基糖苷类对包括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在内的典型革兰氏阳性和革兰氏阴性微生物显示出良好的抗菌活性。
