The general goal of this proposed research is to develop new methods and agents for the treatment of opportunistic infections associated with acquired immune deficiency syndrome (AIDS) and other diseases in which the immune system is compromised. Emphasis will be twofold based on the design and synthesis of ew drugs and the development of new microbe selective antifungal delivery agents based on active iron transport processes that are necessary for the assimilation of physiologically essential iron by pathogens. The general hypotheses to be tested are that new asymmetric synthetic methodology developed in our laboratory will lead to the design of new antifungal agents (and perhaps antiviral agents), and that conjugates of known and new antifungal agents with species specific or selective microbial iron transport agents (siderophores) can be used to target cells of pathogenic organisms or selectively block fungal iron transport and thus inhibit fungal growth. Specific individual aims include; 1) Utilize methodology developed in our laboratory to prepare a library of siderophores and components to determine which siderophores can be recognized and utilized by opportunistic pathogens with initial emphasis on Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus (though many others will be included in broad screening). 2) Synthesize and study siderophore - antifungal agent conjugates to determine if the siderophore can actively transport the antifungal agent (drug) 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 conjugation and/or siderophore-mediated targeting of the drug to fungi. 3) Study the influence and importance of linkers (covalent, including amide, ester, hydrazone, and ionic) between the siderophore and antifungal agent and determine if drug release is necessary or desired. 4) Determine if siderophore conjugates targeted to fungal DNA can induce lethal intracellular DNA scission by reactions associated with the metal of the siderophore component (making antifungal agents from the siderophores themselves). 5) Develop efficient and practical syntheses of novel antifungal agents (and siderophore conjugates) including a) azoxy- containing antifungal agents and nitrone analogs. b) carbocyclic nucleosides and c) peptidyl nucleosides and carbocyclic analogs. Detailed and broad screen biological evaluation of all the antifungal agents and conjugates will help define important structure-activity relationships and demonstrate the tremendous 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 pathogents.
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