The overall goal of this research is to address important problems related to iron assimilation, transport and metabolism that are essential for life. The focus will be on the syntheses and studies of microbial iron chelators (siderophores), analogs and conjugates with antimicrobial agents. The general hypothesis to be tested is that extensions of the studies of microbial iron chelators and transport will facilitate the development of novel therapeutic agents. Specific individual aims are listed below: 1)Apply efficient new methodology for the synthesis of hydroxamic acid components of siderophores by direct oxidation of primary amines. Direct chemical oxidation of primary amines to hydroxylamines, followed by acylation, will provide more effective syntheses of important iron binding components of siderophores and the proposed analogs and conjugates, which can be used as specific enzyme inhibitors, agents for deferration therapy due to iron overload (in thalassemia), inhibitors of lipid peroxidation from ischemia / reperfusion injury, and as components of antimicrobial agents. 2) Complete the synthesis of pseudobactin and specific analogs to determine requirements for iron transport and metabolism in pathogenic strains of Pseudomonas. Well designed analogs and pseudomonal siderophore - drug conjugates are anticipated to be effective antipseudomonal agents. 3) Prepare components of pseudobactin to determine the epitope of antibodies used in the detection of pseudomonal siderophores by one of our collaborators. The hypothesis to be tested is that a portion of the peptide component of pseudobactin is the epitope of antibodies to pseudobactin. 4) Synthesize and study siderophore- and siderophore analog-drug conjugates. The hypothesis to be tested is that the conjugates can use microbial iron transport processes to actively carry antimicrobial agents into cells of pathogenic organisms This concept of siderophore mediated drug delivery will be the major focus of the proposal. 5) Determine the mode of action of the siderophore-drug conjugates. Studies of the interaction of siderophore-antibiotic conjugates with outer membrane receptor proteins, the ability of the conjugates to bind penicillin binding proteins, and the mode of action of the conjugates will facilitate the design of active antimicrobial agents. Together, these studies will enhance the understanding of the essential role of iron in nearly all biological systems and demonstrate the tremendous therapeutic potential from the exploitation of iron complex recognition, transport and metabolic processes.
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