Extra Sugar on Vancomycin: New Analogues for Combating Multidrug-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci
Extra Sugar on Vancomycin: New Analogues for Combating Multidrug-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci
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万古霉素加糖：对抗多重耐药金黄色葡萄球菌和万古霉素耐药肠球菌的新类似物
DOI：
10.1021/acs.jmedchem.7b01345
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发表时间：
2018-01-11
影响因子：
7.3
通讯作者：
Huang, Wei
中科院分区：
文献类型：
--
作者：
Guan, Dongliang;Chen, Feifei;Huang, Wei
万古霉素的亲脂取代是通过增强细菌细胞壁相互作用来开发抗耐药细菌的新型万古霉素类似物的有效策略。然而，疏水结构通常导致较长的消除半衰期和累积毒性；因此，亲水片段也被引入到脂万古霉素中，以调节其药代动力学/药效学性质。在此，我们合成了一系列新的万古霉素类似物，在第7个氨基酸苯环上携带不同的糖基，并在万古胺上进行了亲脂性取代，并进行了广泛的构效关系分析。最佳类似物对甲氧西林敏感金黄色葡萄球菌、万古霉素中间耐药金黄色葡萄球菌（VISA）和万古霉素耐药肠球菌（VRE）的活性较万古霉素高128 ~ 1024倍。体内药代动力学研究表明，脂万古霉素可以有效调节多余的糖基序，缩短半衰期，并解决了脂万古霉素的累积毒性问题。本研究提出了一种有效的脂万古霉素衍生物设计策略，通过引入额外的糖，使其具有更好的抗生素样特性，增强了疗效，优化了药代动力学，降低了毒性。
Lipophilic substitution on vancomycin is an effective strategy for the development of novel vancomycin analogues against drug-resistant bacteria by enhancing bacterial cell wall interactions. However, hydrophobic structures usually lead to long elimination half-life and accumulative toxicity; therefore, hydrophilic fragments were also introduced to the lipo-vancomycin to regulate their pharmacokinetic/pharmacodynamic properties. Here, we synthesized a series of new vancomycin analogues carrying various sugar moieties on the seventh-amino acid phenyl ring and lipophilic substitutions on vancosamine with extensive structure activity relationship analysis. The optimal analogues indicated 128-1024-fold higher activity against methicillin-susceptible S. aureus, vancomycin-intermediate resistant S. aureus (VISA), and vancomycin-resistant Enterococci (VRE) compared with that of vancomycin. In-vivo pharmacokinetics studies demonstrated the effective regulation of extra sugar motifs, which shortened the half-life and addressed concerns of accumulative toxicity of lipo-vancomycin. This work presents an effective strategy for lipo-vancomycin derivative design by introducing extra sugars, which leads to better antibiotic-like properties of enhanced efficacy, optimal pharmacokinetics, and lower toxicity.