Structure-based design, synthesis, and A-site rRNA cocrystal complexes of functionally novel aminoglycoside antibiotics:: C2" ether analogues of paromomycin
Structure-based design, synthesis, and A-site rRNA cocrystal complexes of functionally novel aminoglycoside antibiotics:: C2" ether analogues of paromomycin
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DOI：
10.1021/jm061200
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发表时间：
2007-05-17
影响因子：
7.3
通讯作者：
Westhof, Eric
中科院分区：
文献类型：
--
作者：
Hanessian, Stephen;Szychowski, Janek;Westhof, Eric
基于新的位点选择性功能化反应，合成了一系列巴龙霉素的2“-O-取代醚类似物。几个这样的类似物的X-射线共晶复合物揭示了一种新的模式的结合在A-位点rRNA，环I和II采用了熟悉的方向和位置先前观察到巴龙霉素，但环III和IV的取向不同。除少数例外，所有新的类似物对敏感的S.金黄色。获得针对E.大肠杆菌，与一些醚附件含有极性或碱性端基。两种类似物在小鼠败血症保护试验中显示出优异的存活率。肾脏的初步组织病理学分析显示没有明显的毒性迹象，而新霉素和卡那霉素的对照在较低剂量下是有毒的。
A series of 2 ''-O-substituted ether analogues of paromomycin were prepared based on new site-selective functionalizations. X-ray cocrystal complexes of several such analogues revealed a new mode of binding in the A-site rRNA, whereby rings I and II adopted the familiar orientation and position previously observed with paromomycin, but rings III and IV were oriented differently. With few exceptions, all of the new analogues showed potent inhibitory activity equal or better than paromomycin against a sensitive strain of S. aureus. Single digit mu M MIC values were obtained against E. coli, with some of the ether appendages containing polar or basic end groups. Two analogues showed excellent survival rate in a mouse septicemia protection assay. Preliminary histopathological analysis of the kidney showed no overt signs of toxicity, while controls with neomycin and kanamycin were toxic at lower doses.