The design, synthesis, and evaluation of key analogs of the glycopeptide antibiotics including vancomycin are detailed in efforts that will have a fundamental impact on the understanding and treatment of resistant bacterial infections (e.g. MRSA, VRSA, and VRE). This includes efforts to redesign vancomycin for dual binding to D-Ala-D-Ala and D-Ala-D-Lac to address the emerging bacterial resistance derived from peptidoglycan remodeling of D-Ala-D-Ala, combine successful pocket modified residue 4 analogs with additional peripheral modifications to enhance potency and in vivo efficacy, simplify the core aglycon structure, prepare successful residue 4 modified analogs by semisynthetic and fermentation methods, define and optimize the role of the aryl chlorides, and further explore a new class of glycopeptide derivatives we discovered that are active against VanB resistant bacteria. These studies will establish the consequences of re-engineering vancomycin to bind D-Ala-D-Lac, provide several unique approaches to countering the emerging vancomycin resistance, chart a rational path forward for the development of durable antibiotics for the treatment resistant bacterial infections including MRSA and the feared vancomycin-resistant bacteria (VRSA, VRE), and provide a fundamental understanding of the structure-function relationships of the glycopeptide antibiotics. An exciting complement to these studies is the detailed exploration of ramoplanin that is similarly designed to refine the understanding of its mechanism of action, define the structural details of its binding to lipid II, and establish key structural features contributing to transglycosylase inhibition and antimicrobial activity. Extensions of recently completed studies on the total synthesis of the chloropeptins (anti HIV activity) to an examination of their structure-function properties will be initiated.
Fundamentally new approaches and new therapeutics for the treatment of resistant bacterial infections including MRSA, VRSA, and VRE will emerge from the studies and a fundamental understanding of the mechanism of action and the interaction of biologically active natural products with their biological targets will be developed.
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