Novel antifungals for Immunocompromised/HIV patients.

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DESCRIPTION (provided by applicant): Fungal infections continue to be a major cause of morbidity and mortality among HIV- infected patients. At present, there are only three classes of antifungal agents that are suitable for the treatment of AIDS-related fungal infections, but these medications are hampered by drug resistance, pharmacological limitations, and negative drug interactions. Also, the challenge continues to complicate by a changing epidemiology of fungal pathogen. The search for new scaffolds with broad antifungal activity is imperative. Antifungal compounds have been discovered from natural products. For examples, glucan synthesis inhibitors (including pnemoncandins, other echinocandins) have been found in a diverse range of fungi. These compounds have come from fermentation broths of soil samples cultured in sterile conditions. Since complicated environmental conditions are critical for the synthesis of most microbial secondary metabolites screening compounds produced under sterile laboratory conditions frequently results in the rediscovery of known compounds that are readily produced under those conditions. LifePharms, Inc. has established a collection of field- collected, environmentally challenged fruiting bodies that consists currently of greater than 26,000 samples of basidiomycetes and ascomycetes (those that have a fruiting body) and includes nearly every species found in the continental United States. LifePharms' bank of extracts from fruiting bodies of basidiomycetes and ascomycetes is unmatched for its uniqueness and for its chemical diversity. In collaboration with the Antifungal Susceptibility Testing Laboratory and Division of Infectious Diseases at the University of Texas Health Science Center at San Antonio (UTHSCSA), we are screening LifePharms' natural product library against both fluconazole sensitive (ATCC 90028) and resistant Candida strains ATCC 90030, 96901, 6852) and Aspergillus fumigatus and Cryptococcus neoformans. The active compounds in LifePharms' are separated by a single HPLC step and screened for antifungal activity and mammalian toxicity. Those semipure compounds with activity against at least two drug resistant fungal strains with no mammalian toxicity will be purified by high speed counter current chromatography and HPLC. Compounds will be dereplicated and chemically characterized by NMR and LC/MS/MS methods. The MICs will be determined against a broad range of clinical isolates and will include species that are important causes of systemic infections in humans, including immunocompetent and immunocompromised hosts, including Pneumocystis. Structurally novel compounds with a unique in vitro antifungal profile will be selected for ADMET and in vivo evaluation in Phase II. PUBLIC HEALTH RELEVANCE: Fungal infections continue to be a major cause of morbidity and mortality among HIV-infected patients. Antifungal compounds have been discovered from natural products. In collaboration with the Antifungal Susceptibility Testing Laboratory and Division of Infectious Diseases at the University of Texas Health Science Center at San Antonio, we are screening LifePharms' natural product library against both fluconazole sensitive and resistant Candida strains, and Aspergillus fumigatus and Cryptococcus neoformans.