期刊
CHEMMEDCHEM
卷 13, 期 16, 页码 1644-1657出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201800252
关键词
antibacterial activity; click chemistry; Mannich reaction; pyrophosphate; vancomycin
资金
- National Natural Science Foundation of China (NNSFC) [21572244]
- SIMM institute fund [CASIMM0120162014, CASIMM0120164007]
- Youth Innovation Promotion Association of CAS [2017328]
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.
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