Fungal infections are a serious problem in the clinical management of AIDS patients. Without treatment targeted to the pathogenic fungi, they are often fatal to AIDS patients. The long term objectives of this project are to determine and understand the basic mechanism of action of the cell wall effects of bleomycin on the AIDS opportunistic fungal pathogen, Candida albicans.
The specific aims are to determine some of the cellular, molecular and biochemical bases for cell wall effects of bleomycin in C. albicans, and determine which components of the C. albicans cell wall react with bleomycin. Using several experimental approaches, we will determine the range of susceptibilities of C. albicans isolates to killing, cell wall damage, and chromosomal breaks caused by bleomycin treatments, and determine specific changes in the cell wall associated with bleomycin treatments using transmission electron microscopy, biochemical studies of cell wall components, and pulsed-field gel electrophoresis for assays of DNA breaks and electrophoretic karyotyping. The research is designed to determine the basic mechanism of the antifungal action f bleomycin on C. albicans cell walls. This basic information should lead to an understanding of the basic biology of C. albicans isolates and therapeutic usefulness of low doses of bleomycin or an analog as an antifungal for acute treatments. Low doses of the drug or an analog may be able to be used as a single agent or in one or more drug combinations, particularly when C. albicans develops resistance to another antifungal drug. The information from this research should also lead to the identification of potential target structures for additional antifungal drugs and assist in antifungal drug design and therapy to target critical structures.
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