Synthesis and Biological Evaluation of Vancomycin Dimers with Potent Activity against Vancomycin-Resistant Bacteria: Target-Accelerated Combinatorial Synthesis

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 Ac2‐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. A number of highly potent antibiotics have been identified in the screening of compound libraries based on the notion that dimerization (an example is shown here) and/or variation of amino acid one of vancomycin could potentially enhance biological activity.