The broad, long-term objectives of this research program are to better understand, and to improve and expand upon the functions of receptor-like antibacterial agents.
The specific aims of the proposed studies are 1) to explore the potential for increasing the potency of glycopeptide antibiotics through covalent multimerization and other modifications, 2) to develop a combinatorial approach to enhancing binding interactions between vancomycin and its target ligands in both vancomycin-susceptible and vancomycin-resistant bacteria, and 3) to carry out the first systematic structure/function analysis of the bacitracin family of antibacterial agents. It is clear that novel and improved antibiotics and therapeutic approaches are needed to meet the serious threats to health posed by the emergence of multiply drug-resistant bacterial pathogens. The relevance of the proposed work derives from its focus on gaining a more detailed understanding of the modes of action of important antibacterial agents, and using this information to address limitations and challenges to antibiotic use. Covalently linked multimers of vancomycin and ristocetin A will be prepared by semisynthetic elaboration of the parent antibiotics. Spectroscopic methods will be used to quantify the interactions between these derivatives and peptide and depsipeptide ligands which mimic their cellular targets. The relationships among degree of multimerization, molecular recognition properties, and antibacterial activities for these compounds will be determined. Combinatorial libraries of support-bound vancomycin-peptide conjugates will be prepared by solid-phase synthesis, and screened for members which exhibit enhanced binding affinity for peptide and depsipeptide ligands. This work is directed towards testing the hypothesis that vancomycin derivatives which bind more tightly to peptidoglycan precursors will exhibit greater antibacterial potency. Derivatives of bacitracin A will be prepared by total synthesis, and used to define the role(s) played by functional groups of this antibiotic in binding to metal ions, binding to its cellular target, and in exerting antibacterial properties.