Design and Synthesis of Pyrophosphate‐Targeting Vancomycin Derivatives for Combating Vancomycin‐Resistant Enterococci. (17th July 2018)

• Record Type: Journal Article
• Authors: Guan, Dongliang; Chen, Feifei; Faridoon, ; Liu, Junjie; Li, Jian; Lan, Lefu; Huang, Wei
• Is Part Of: ChemMedChem. Volume 13:Number 16(2018)
• Page Start: 1644
• Page End: 1657
• Publication Date: 2018-07-17
• Subjects: antibacterial activity -- click chemistry -- Mannich reaction -- pyrophosphate -- vancomycin; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201800252
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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. Compound11 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. Abstract : The advantages of synergy : The introduction of an optimal pyrophosphate‐targeting moiety in the structure of vancomycin enhanced the antibacterial activity >32‐fold over vancomycin itself against vancomycin‐resistant Enterococci (VRE), and the appropriate location of a hydrophobic tail group provided a synergistic effect (>128‐fold higher activity than vancomycin) in antibacterial activity assays against VRE.