Fungal transporters: from resistance to new antifungals

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DESCRIPTION (provided by applicant): Oral candidiasis, caused by the opportunistic fungal pathogen Candida albicans, affects many people - from the newborn to elderly denture wearers. The most serious mucosal infections, including oropharyngeal candidiasis, are seen in immunocompromised individuals such HIV/AIDS patients, and life-threatening disseminated infections affect organ transplant recipients. Treatment currently relies heavily on the azole antifungals such as fluconazole. Antifungal treatment of patients is hampered by the paucity of antifungal agents, currently available, and by the incidence of azole drug resistance. Azole resistance in C. albicans is often caused by hyper-expression of plasma membrane efflux pumps. Our long-term goal is to improve the treatment of patients with opportunistic fungal infections by discovering new classes of antifungal agents. Our hypotheses are that inhibitors of fungal efflux pumps, such as CaCdr1p, will sensitize C. albicans to existing antifungals, and that drug efflux can also be overcome by inhibiting the plasma membrane proton pump CaPma1p that supplies the energy for drug efflux. This project combines a fundamental study of membrane pump function with structure-directed drug discovery. The specific aims are to: 1. Validate drug targets and identify intra-molecular sites affecting fungal membrane pump function. Drug target sites will be identified by correlating changes in membrane pump sequences with the function of pumps responsible for clinical drug resistance and by the structural analysis of CaCdr1p and CaPma1p. 2. Optimize inhibitors of drug efflux pumps. A lead peptide inhibitor of CaCdr1p will be optimized and novel broad-spectrum peptide pump inhibitors with high in vitro and in vivo activities and low host toxicity will be identified. 3. Develop non-peptide inhibitors of CaCdr1p and CaPma1p. Interactions of lead inhibitors with their target proteins will guide the screening of compound libraries for non-peptide inhibitors that may be of greater therapeutic value. This project will increase our understanding of efflux pump structure and function and identify pump inhibitors that could lead to new therapies for patients with opportunistic fungal infections.