The overall goals of this research are to demonstrate the potential of microbial iron transport-mediated drug delivery and to address important problems related to iron assimilation, transport, and metabolism that are essential for life. The general hypothesis to be tested is that syntheses and studies of microbial iron chelators (siderophores), analogs and conjugates with antimicrobial agents will facilitate the design of novel, actively transported, microbially selective therapeutic agents for the treatment of infections due to pathogenic organisms. The siderophore-based """"""""Trojan Horse"""""""" drug conjugates also have the potential to alter normal modes of assimilation and renew effectiveness of previous drugs to which resistance has developed.
Specific aims i nclude: 1) Develop new chemical methods for the practical syntheses of siderophore components. 2) Apply the methodology to the design and syntheses of specific siderophores, analogs and drug conjugates. The hypotheses to be tested are: a) Syntheses of pseudobactin, analogs and drug conjugates will provide new therapies for treatment of pathogenic pseudomonal infections. b) Syntheses of mycobactins, analogs and drug conjugates will provide entirely new approaches to the treatment of mycobacterial infections, including tuberculosis. c) Syntheses of newly discovered siderophores, alterobactins A and B, and analogs will allow determination of the postulated """"""""perfect fit"""""""" of the novel siderophore structure to account for the extremely high affinity of these compounds for iron. The result will facilitate the design of new siderophore analogs and drug conjugates for potential therapeutic use. d) Syntheses of polyamine- based catechol-containing siderophore-drug conjugates, trihydroxamate peptide-based conjugates, and mixed-ligand siderophore-drug conjugates with drugs of varying modes of action will help determine important structure-activity relationships for siderophore-mediated drug delivery. e) Syntheses of citrate and isocyanurate-based siderophore drug conjugates will facilitate incorporation of more than one drug and drug type into a single siderophore delivery system to determine the effectiveness of """"""""multiple warhead"""""""" drug delivery agents. f) Syntheses of specific desferal-DNA intercalating agents will lead to development of new antimalarial agents. 3) Characterize completely each of the synthetic siderophores, components and drug conjugates and determine their iron binding affinities to facilitate SAR studies. 4) Verify that siderophore analogs can be used as non-toxic organ selective (e.g. liver and kidney) MRI contrast agents. 5) Perform detailed biological studies to determine the mode of action of antimicrobial siderphore analogs and conjugates to conform the feasibility of siderphore-mediated drug delivery and facilitate long term SAR studies.
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