Vancomycin and bacitracin are peptide-derived natural products which exert antibacterial activity via inhibition of peptidoglycan biosynthesis. Vancomycin and bacitracin share an interesting property -- their targets are not macromolecules such as proteins and nucleic acids, but rather intermediates in peptidoglycan biosynthesis. Vancomycin and bacitracin bind to their targets (the C-terminal portion of peptidoglycan precursors in the case of vancomycin, and bactoprenyl pyrophosphate in the case of bacitracin), which effectively sequesters them from the cellwall biosynthesis machinery. We have undertaken a research program to synthesize and/or semisynthetically modify these agents, with three goals in mind: 1) to enhance binding to cellular targets, 2) to endow them with specific targetting activities, and 3) to endow them with catalytic activity. We believe that such modifications may enhance the potency and/or range of efficacy of these antibiotics. To date, we have developed general methods for the semisynthesis of vancomycin carboxamides, and undertaken the total synthesis of bacitracins. We have discovered unprecedented carbamate hydrolase activity by vancomycin and related glycopeptide antibacterial agents, and developed novel methods for probing microenvironments within glycopeptide:peptide complexes. Some of our vancomycin carboxamide derivatives exhibit enhanced antibacterial potency relative to vancomycin, including promising activity against vancomycin-resistant enterococci. In these and our planned future studies, FAB-MS and related techniques are critical to proper structural characterization of synthetic structures.
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