New Broad-Spectrum Antibacterial Amphiphilic Aminoglycosides Active against Resistant Bacteria: From Neamine Derivatives to Smaller Neosamine Analogues
New Broad-Spectrum Antibacterial Amphiphilic Aminoglycosides Active against Resistant Bacteria: From Neamine Derivatives to Smaller Neosamine Analogues
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DOI：
10.1021/acs.jmedchem.6b00818
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发表时间：
2016-10-27
影响因子：
7.3
通讯作者：
Decout, Jean-Luc
中科院分区：
文献类型：
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作者：
Zimmermann, Louis;Das, Indrajit;Decout, Jean-Luc
氨基糖苷类抗生素是一类广谱、强效的抗生素，通过与16 S rRNA的A位点结合而干扰蛋白质合成。数十年来AG的广泛临床使用通过选择耐药细菌强烈降低了其临床疗效。最近，亲脂性基团与AG的缀合产生了一类新的有效的抗菌两亲性氨基糖苷类（AAGs），其对各种敏感和耐药细菌菌株具有显著改善的活性。我们已经鉴定了小氨基糖苷新霉胺的两亲性3 '，6-二烷基衍生物作为靶向细菌膜的广谱抗菌剂。在这里，我们报告的合成和对敏感和耐药革兰氏阴性和/或革兰氏阳性细菌的新的两亲性3 '，4'-二烷基新霉胺衍生物和它们的较小的类似物在6-氨基葡萄糖胺（新霉胺）系列从N-乙酰葡糖胺制备的活性。
Aminoglycosides (AGs) constitute a major family of potent and broad-spectrum antibiotics disturbing protein synthesis through binding to the A site of 16S rRNA. Decades of widespread clinical use of AGs strongly reduced their clinical efficacy through the selection of resistant bacteria. Recently, conjugation of lipophilic groups to AGs generated a novel class of potent antibacterial amphiphilic aminoglycosides (AAGs) with significant improved activities against various sensitive and resistant bacterial strains. We have identified amphiphilic 3',6-dialkyl derivatives of the small aminoglycoside neamine as broad spectrum antibacterial agents targeting bacterial membranes. Here, we report on the synthesis and the activity against sensitive and resistant Gram-negative and/or Gram-positive bacteria of new amphiphilic 3',4'-dialkyl neamine derivatives and of their smaller analogues in the 6-aminoglucosamine (neosamine) series prepared from N-acetylglucosamine.