Elucidation of the Active Conformation of Vancomycin Dimers with Antibacterial Activity against Vancomycin‐Resistant Bacteria

Abstract

Covalently linked vancomycin dimers have attracted a great deal of attention among researchers because of their enhanced antibacterial activity against vancomycin-resistant strains. However, the lack of a clear insight into the mechanisms of action of these dimers hampers rational optimization of their antibacterial potency. Here, we describe the synthesis and antibacterial activity of novel vancomycin dimers with a constrained molecular conformation achieved by two tethers between vancomycin units. Conformational restriction is a useful strategy for studying the relationship between the molecular topology and biological activity of compounds. In this study, two vancomycin units were linked at three distinct positions of the glycopeptide (vancosamine residue (V), C terminus (C), and N terminus (N)) to form two types of novel vancomycin cyclic dimers. Active NC-VV-linked dimers with a stable conformation as indicated by molecular mechanics calculations selectively suppressed the peptidoglycan polymerization reaction of vancomycin-resistant Staphylococcus aureus in vitro. In addition, double-disk diffusion tests indicated that the antibacterial activity of these dimers against vancomycin-resistant enterococci might arise from the inhibition of enzymes responsible for peptidoglycan polymerization. These findings provide a new insight into the biological targets of vancomycin dimers and the conformational requirements for efficient antibacterial activity against vancomycin-resistant strains.

Regulation of Resistance in Vancomycin-Resistant Enterococci: The VanRS Two-Component System

“…Despite this large body of evidence favoring an indirect-detection model for VanS A , evidence also exists supporting a direct-binding model [216][217][218][219][220][221]. A sedimentation-velocity experiment performed using detergent-solubilized VanS A revealed a shift in the sedimentation coefficient of VanS A in the presence of vancomycin, suggesting that vancomycin induces a conformational change in the protein, presumably via a direct interaction [222,223].…”

Binding Properties of Antimicrobial Agents to Lipid Membranes Using Surface Plasmon Resonance

“…17) Various vancomycin analogs have been synthesized and their antimicrobial activities have been estimated and characterized. [37][38][39][40] Van-M-02 (Fig. 1), synthesized as a glycopeptide inhibitor of peptidoglycan synthesis, has activities against Gram-positive bacteria including VRE.…”

“…1) synthesized as vancomycin dimers exhibit strong activity against vancomycin-resistant bacteria. [38][39][40] Representative sensorgrams presented in Fig. 2 showed few interactions of vancomycin, Dimer 2, teicoplanin, erythromycin and linezolid with the POPC, POPG, POPG/CL (1 : 1, v/v) and POPE/POPG (4 : 1, v/v) liposome membranes immobilized on the Sensor Chip L1 using 2×PBS containing 5% DMSO as a running buffer.…”

N-doped carbon nanosheets with antibacterial activity: mechanistic insight

“…30 Dispersed graphene based materials are known to display strong antibacterial activity. [43][44][45] However, to the best of our knowledge, the antibacterial activity of CNS has not yet been explored. 37 Carbon nanosheets (CNS), which comprise multi-layered graphene lms are a new class of carbon material and possess high surface to volume ratio, sharp edge plane defects and lightness with higher efficacy compared to graphene.…”