Fungal transporters: from resistance to new antifungals

描述（由申请人提供）：口腔念珠菌病，由机会性真菌病原体白色念珠菌引起，影响许多人-从新生儿到老年假牙佩戴者。最严重的粘膜感染，包括口咽念珠菌病，见于免疫功能低下的个体，如艾滋病毒/艾滋病患者，危及生命的播散性感染影响器官移植受者。目前的治疗主要依赖于氟康唑等抗真菌药物。患者的抗真菌治疗受到目前可用的抗真菌药物的缺乏和唑类药物耐药性的影响。白色念珠菌耐唑常由质膜外排泵的高表达引起。我们的长期目标是通过发现新的抗真菌药物来改善机会性真菌感染患者的治疗。我们的假设是真菌外排泵的抑制剂，如CaCdr1p，会使白色念珠菌对现有的抗真菌药物敏感，并且药物外排也可以通过抑制为药物外排提供能量的质膜质子泵CaPma1p来克服。这个项目结合了膜泵功能的基础研究和结构导向药物的发现。具体目标是：

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.