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Insights into Key Interactions between Vancomycin and Bacterial Cell Wall Structures
ACS Omega ( IF 4.1 ) Pub Date : 2018-01-04 00:00:00 , DOI: 10.1021/acsomega.7b01483
Feng Wang 1 , Hongyu Zhou 1 , Olatunde P. Olademehin 2 , Sung Joon Kim 2 , Peng Tao 1
Affiliation  

Vancomycin is a glycopeptide antibiotic used for the treatment of serious infections by Gram-positive pathogens. Vancomycin inhibits cell wall biosynthesis by targeting the d-Ala-d-Ala terminus of peptidoglycan (PG). The highly cross-linked heptapeptide aglycon structure of vancomycin is the d-Ala-d-Ala binding site. The first residue of vancomycin is N-methyl-leucine, which is crucial for the dipeptide binding. The removal of N-methyl-leucine by Edman degradation results in desleucyl-vancomycin devoid of antimicrobial activities. To investigate the function of N-methyl-leucine for the dipeptide binding in vancomycin, molecular dynamics simulations of vancomycin and three N-terminus-modified vancomycin derivatives: desleucyl-vancomycin, vancomycinNtoC, and vancomycinSar, binding to a PG unit of the sequence l-Ala-d-iso-Gln-l-Lys-d-Ala-d-Ala with an intact pentaglycine bridge structure attached to the bridge link of l-Lys were carried out. Glycopeptide–PG binding interactions were characterized by root-mean-square-deviation contour analysis of atomic positions in vancomycin and its three analogues bound to a PG unit. The overall sampling space for four glycopeptide–PG complexes shows four distinct distributions with a continuous change between the conformational spaces. The hydrogen bond analyses show that multiple hydrogen bonds between the d-Ala-d-Ala and the vancomycin aglycon structure strengthened the dipeptide binding. The simulations revealed that the removal or chemical modification of N-methyl-leucine significantly weakens the dipeptide binding to the aglycon structure and provides interesting structural insights into glycopeptide–PG binding interactions.

中文翻译:

深入了解万古霉素与细菌细胞壁结构之间的关键相互作用

万古霉素是一种糖肽抗生素,用于治疗革兰氏阳性病原体的严重感染。万古霉素通过靶向肽聚糖(PG)的d -Ala- d -Ala末端来抑制细胞壁的生物合成。万古霉素的高度交联的七肽糖苷配基结构是d -Ala- d -Ala结合位点。万古霉素的第一个残基是N-甲基亮氨酸,对二肽结合至关重要。通过Edman降解去除N-甲基-亮氨酸会导致去糖基-万古霉素缺乏抗菌活性。研究N的功能-甲基亮氨酸用于万古霉素中的二肽结合,万古霉素和三种N末端修饰的万古霉素衍生物:去氨酰-万古霉素,万古霉素NtoC和万古霉素Sar的分子动力学模拟,与序列l -Ala- d的PG单元结合-iso-Gln- l -Lys- d -Ala- d -Ala,其完整的五甘氨酸桥结构连接到l的桥链上-进行了测谎。糖肽-PG结合相互作用的特征是通过对万古霉素及其与PG单元结合的三个类似物的原子位置进行均方根偏差轮廓分析。四个糖肽-PG复合物的总采样空间显示出四个不同的分布,并且构象空间之间连续变化。氢键分析表明,d -Ala- d -Ala与万古霉素糖苷配基结构之间的多个氢键增强了二肽结合。模拟结果表明,N-甲基亮氨酸的去除或化学修饰大大削弱了二肽与糖苷配基的结合,并为糖肽-PG的结合相互作用提供了有趣的结构见解。
更新日期:2018-01-04
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