Design and Synthesis of Pyrophosphate-Targeting Vancomycin Derivatives for Combating Vancomycin-Resistant Enterococci
Design and Synthesis of Pyrophosphate-Targeting Vancomycin Derivatives for Combating Vancomycin-Resistant Enterococci
复制标题
用于对抗万古霉素耐药肠球菌的焦磷酸盐靶向万古霉素衍生物的设计与合成
DOI：
10.1002/cmdc.201800252
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发表时间：
2018-08-20
期刊：
影响因子：
3.4
通讯作者：
Huang, Wei
中科院分区：
文献类型：
--
作者：
Guan, Dongliang;Chen, Feifei;Huang, Wei
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 lipidII 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 11b (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.
