School of Pharmacy, Jinzhou Medical University, Jinzhou 121001, PR China; CAS Key Laboratory of Receptor Research, CAS Center for Excellence in Molecular Cell Science, Center for Biotherapeutics Discovery Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, PR China.
CAS Key Laboratory of Receptor Research, CAS Center for Excellence in Molecular Cell Science, Center for Biotherapeutics Discovery Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, PR China; Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, Hengyang, Hunan 421001, China.
Bioorg Med Chem Lett. 2021 Jun 15;42:128027. doi: 10.1016/j.bmcl.2021.128027. Epub 2021 Apr 9.
Over 60-year clinical use of vancomycin led to the emergence of vancomycin-resistant bacteria and threatened our health. To combat vancomycin-resistant strains, numerous vancomycin analogues were developed, such as Telavancin, Oritavancin and Dalbavancin. Extra structures embedded on C-terminus has been proved to be an effective strategy to promote antibacterial activity of vancomycin against vancomycin-resistant strains. Here, we reported a facile strategy, inspired by native chemical ligation, for vancomycin C-terminus functionalization and derivatization. The introduction of C-terminal hydrazide on vancomycin not only provided us an accessible method for C-terminus functionalization through carbonyl azide and thioester, also acted as an efficient site for vancomycin structure modifications. Based on hydrazide-vancomycin, we effectively conjugated cysteine and cysteine containing peptides onto vancomycin C-terminus, and two fluorescent FITC-vancomycin were prepared through Cys-Maleimide conjugation. Meanwhile, we introduced lipophilic structures onto vancomycin C-terminus via the hydrazide moiety. The obtained vancomycin derivatives were evaluated against both Gram-positive and negative bacteria strains.
万古霉素经过超过 60 年的临床应用，导致了耐万古霉素细菌的出现，威胁着我们的健康。为了对抗耐万古霉素的菌株，开发了许多万古霉素类似物，如特拉万星、奥他万星和达巴万星。在 C 末端嵌入额外的结构已被证明是提高万古霉素对耐万古霉素菌株抗菌活性的有效策略。在这里，我们受天然化学连接的启发，报道了一种用于万古霉素 C 末端功能化和衍生化的简便策略。在万古霉素上引入 C 末端酰肼不仅为我们提供了通过羰基叠氮化物和硫酯进行 C 末端功能化的一种便捷方法，也为万古霉素结构修饰提供了一个有效的位点。基于酰肼-万古霉素，我们有效地将半胱氨酸和含半胱氨酸的肽连接到万古霉素的 C 末端，并通过 Cys-Maleimide 缀合制备了两种荧光 FITC-万古霉素。同时，我们通过酰肼部分将亲脂结构引入到万古霉素的 C 末端。对所得到的万古霉素衍生物进行了革兰氏阳性和革兰氏阴性细菌的活性评价。
