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Design and Synthesis of Pyrophosphate‐Targeting Vancomycin Derivatives for Combating Vancomycin‐Resistant Enterococci
Author(s) -
Guan Dongliang,
Chen Feifei,
Liu Junjie,
Li Jian,
Lan Lefu,
Huang Wei
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800252
Subject(s) - vancomycin , lipid ii , pyrophosphate , glycopeptide , peptidoglycan , chemistry , glycopeptide antibiotic , moiety , dipeptide , biochemistry , microbiology and biotechnology , in vitro , antibiotics , combinatorial chemistry , bacteria , stereochemistry , amino acid , biology , cell wall , staphylococcus aureus , enzyme , genetics
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.