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Elucidation of the Active Conformation of Vancomycin Dimers with Antibacterial Activity against Vancomycin‐Resistant Bacteria
Author(s) -
Nakamura Jun,
Yamashiro Hidenori,
Hayashi Sayaka,
Yamamoto Mami,
Miura Kenji,
Xu Shu,
Doi Takayuki,
Maki Hideki,
Yoshida Osamu,
Arimoto Hirokazu
Publication year - 2012
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201201211
Subject(s) - vancomycin , peptidoglycan , glycopeptide , antibacterial activity , chemistry , covalent bond , bacteria , stereochemistry , biochemistry , staphylococcus aureus , combinatorial chemistry , enzyme , antibiotics , biology , organic chemistry , genetics
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.