CAS Key Laboratory of Receptor Research, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai, 201203, P.R. China.
University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, P.R. China.
ChemMedChem. 2018 Aug 20;13(16):1644-1657. doi: 10.1002/cmdc.201800252. Epub 2018 Jul 17.
As the last resort for intractable Gram-positive bacterial infections, vancomycin is losing efficacy with the emergence of vancomycin-resistant bacteria, especially vancomycin-resistant Enterococci (VRE). To combat this threat, we rationally designed and synthesized 39 novel vancomycin derivatives by respective or combined modifications using metal-chelating, lipophilic, and galactose-attachment strategies for extensive structure-activity relationship (SAR) analysis. In a proposed mechanism, the conjugation of dipicolylamine on the seventh amino acid resorcinol position or C-terminus endowed the vancomycin backbone with binding capacity for the pyrophosphate moiety in lipid II while maintaining the intrinsic binding affinity for the dipeptide terminus of the bacterial cell wall peptidoglycan precursor. The in vitro antibacterial activities were evaluated, and the optimal compounds indicated 16- to 1024-fold higher activity against VRE than that of vancomycin. Compound 11 b (3',5'-bis(dipicolylaminomethyl)tyrosine [1,2,3]triazolylmethoxylethyoxyl ethylaminomethyl-N-decylvancomycin) was found to have particularly potent activity against VRE through synergistic effects brought about by combining two peripheral modifications.
作为治疗耐药革兰阳性菌感染的最后手段，万古霉素的疗效因耐万古霉素细菌（VRE）的出现而逐渐减弱。为了应对这一威胁，我们采用金属螯合、亲脂性和半乳糖附着等策略，通过分别或联合修饰，合理设计并合成了 39 种新型万古霉素衍生物，进行了广泛的构效关系（SAR）分析。在提出的机制中，在第七个氨基酸间苯二酚位置或 C 末端接上二吡啶甲胺，使万古霉素骨架具有与脂质 II 中焦磷酸部分结合的能力，同时保持与细菌细胞壁肽聚糖前体中二肽末端的内在结合亲和力。对这些化合物进行了体外抗菌活性评估，结果表明，优化后的化合物对 VRE 的活性比万古霉素高 16 至 1024 倍。化合物 11b（3'，5'-双（二吡啶甲胺基甲基）酪氨酸[1,2,3]三唑基甲氧基乙氧基乙基氨甲基-N-癸基万古霉素）通过两种外围修饰的协同作用，对 VRE 具有特别强的活性。
