Synthesis and biological evaluation of vancomycin dimers with potent activity against vancomycin-resistant bacteria: target-accelerated combinatorialsynthesis

Based on the notion that dimerization and/or variation of amino acid 1 of v ancomycin could potentially enhance biological activity, a series of synthe tic and chemical biology studies were undertaken in order to discover poten t 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. combinator ial 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 l ibraries led to the identification of a number of highly potent antibiotics effective against vancomycin-suspectible, vancomycin-intermediate resistan t and, most significantly, vancomycin-resistant bacteria.