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Synthesis and Biological Evaluation of Vancomycin Dimers with Potent Activity against Vancomycin‐Resistant Bacteria: Target‐Accelerated Combinatorial Synthesis
Author(s) -
Nicolaou K. C.,
Hughes Robert,
Cho Suk Young,
Winssinger Nicolas,
Labischinski Harald,
Endermann Rainer
Publication year - 2001
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 - 10.1002/1521-3765(20010903)7:17<3824::aid-chem3824>3.0.co;2-1
Subject(s) - vancomycin , bacteria , chemistry , microbiology and biotechnology , combinatorial chemistry , biology , staphylococcus aureus , genetics
Based on the notion that dimerization and/or variation of amino acid 1 of vancomycin could potentially enhance biological activity, a series of synthetic and chemical biology studies were undertaken in order to discover potent antibacterial agents. Herein we describe two ligation methods (disulfide formation and olefin metathesis) for dimerizing vancomycin derivatives and applications of target‐accelerated combinatorial synthesis (e.g. combinatorial synthesis in the presence of vancomycin's target Ac 2 ‐ L ‐Lys‐ D ‐Ala‐ D ‐Ala) to generate libraries of vancomycin dimers. Screening of these compound libraries led to the identification of a number of highly potent antibiotics effective against vancomycin‐suspectible, vancomycin‐intermediate resistant and, most significantly, vancomycin‐resistant bacteria.