The general goal of this proposed research is to develop new methods and agents for the treatment of opportunistic infections associated with AIDS and other diseases in which the immune system is compromised. Emphasis will be on the design and synthesis of new antifungal drugs and the development of new microbe selective antifungal delivery agents based on active iron transport processes that are necessary for assimilation of physiologically essential iron by pathogens. The general hypotheses to be tested are that the recently developed synthetic methods of the applicant will lead to the design of new antifungal agents (and perhaps other therapeutic agents), and that conjugates of antifungal agents with species selective microbial iron transport agents (siderophores) can be used to actively transport antifungal agents into cells of pathogenic organisms or that selective blockage of fungal iron trasport will inhibit fungal growth. Specific individual aims include: 1) Utilize methods developed by the applicant to prepare a library of siderophores and components to determine which can be recognized and used by opportunistic pathogens such as Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus (though many others will be included in broad screening). 2) Determine if modified forms of siderophores can block iron assimilation by select pathogens and lead to the development of new antimicrobial agents with a novel mode of action by inducing iron starvation. 3) Synthesize and study siderophore- antifungal agent conjugates, including """"""""multiwarhead"""""""" conjugates, to determine if they can actively transport antifungal agents (drugs) into the cell or anchor the siderophore-drug conjugate in the cell membrane and, in either case, exert a lethal effect. Known and novel antifungal agents with various modes of action will be conjugated to the siderophores to determine a) optimal microbial selectivity and b) if mammalian toxicity of some drugs can be reduced by siderophore-mediated targeting of the drug to fungi. 4) Study the influence and importance of linkers [covalent (including amide, ester, hydrazone, oxime), ionic and novel """"""""microbe triggered"""""""" release processes] between the siderophores and antifungal agents and determine if drug release is necessary. 5) Develop efficient syntheses of novel antifungal agents (and conjugates) including a) forms of potent antifungal neoenactins, b) carbocyclic nucleosides, c) peptidyl nucleosides and carbocyclic analogs, and d) novel """"""""self delivering"""""""" antisense oligonucleotides. Detailed broad screen biological evaluation of all the antifungal agents and conjugates will help define important structure-activity relationships to demonstrate the therapeutic potential of microbially- targeted iron transport-mediated design of antifungal agents while enhancing the understanding of the essential role of iron assimilation and metabolism for virulence of opportunistic pathogens.
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