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N-Terminus Alkylation of Vancomycin: Ligand Binding Affinity, Antimicrobial Activity, and Site-Specific Nature of Quaternary Trimethylammonium Salt Modification
ACS Infectious Diseases ( IF 5.3 ) Pub Date : 2018-08-01 00:00:00 , DOI: 10.1021/acsinfecdis.8b00152
Zhi-Chen Wu 1 , Nicholas A. Isley 1 , Dale L. Boger 1
Affiliation  

A series of vancomycin derivatives alkylated at the N-terminus amine were synthesized, including those that contain quaternary trimethylammonium salts either directly at the terminal amine site or with an intervening three-carbon spacer. The examination of their properties provides important comparisons with a C-terminus trimethylammonium salt modification that we recently found to improve the antimicrobial potency of vancomycin analogues through an added mechanism of action. The N-terminus modifications disclosed herein were well-tolerated, minimally altering model ligand binding affinities (d-Ala-d-Ala) and antimicrobial activity, but did not induce membrane permeabilization that was observed with a similar C-terminus modification. The results indicate that our earlier observations with the C-terminus modification are sensitive to the site as well as structure of the trimethylammonium salt modification and are not simply the result of nonspecific effects derived from introduction of a cationic charge.

中文翻译:

万古霉素的N末端烷基化:配体结合亲和力,抗菌活性和季三甲基铵盐修饰位点的特定性质。

合成了一系列在N末端胺上烷基化的万古霉素衍生物,包括那些直接在末端胺位处或带有插入的三碳间隔基的季三甲基铵盐。检查它们的性质可提供与C端三甲基铵盐修饰物的重要比较结果,我们最近发现该修饰物通过增加的作用机理提高了万古霉素类似物的抗菌效力。本文公开的N末端修饰具有良好的耐受性,最小程度地改变了模型配体结合亲和力(d- Ala- d-Ala)和抗菌活性,但没有诱导膜通透性,而C端修饰类似。结果表明,我们早期的C末端修饰对三甲基铵盐修饰的位点和结构均敏感,而不仅仅是由于引入阳离子电荷而产生的非特异性作用的结果。
更新日期:2018-08-01
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