Novel antifungals for Immunocompromised/HIV patients.

适用于免疫功能低下/艾滋病毒患者的新型抗真菌药物。

• 批准号: 8210874
• 负责人: Esteban Edward Mena
• 金额: $ 30万
• 依托单位: LIFEPHARMS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8210874
• 关键词: Acquired Immunodeficiency Syndrome; Antifungal Agents; Ascomycota; Aspergillus; Aspergillus fumigatus; Basidiomycota; Biological Factors; COSY; Candida; Candida albicans; Candidiasis; Carbon; Cells; Chemicals; Chromatography; Clinical; Collaborations; Collection; Communicable Diseases; Cryptococcus; Cryptococcus neoformans; Drug Interactions; Drug resistance; Epidemiology; Evaluation; Fermentation; Fluconazole; Fluconazole resistance; Fractionation; Fruit; Glucans; Goals; HIV; Health Sciences; High Pressure Liquid Chromatography; Human; Immunocompetent; Immunocompromised Host; In Vitro; Incidence; Inhibitory Concentration 50; Laboratories; Libraries; MCF7 cell; Mammalian Cell; Methods; Morbidity - disease rate; Mycoses; Patients; Pharmaceutical Preparations; Phase; Pneumocystis; Predisposition; Preparation; Protons; Resistance; Sampling; Screening procedure; Speed; Sterility; Systemic infection; Testing; Texas; Toxic effect; United States; Universities; base; fungus; in vitro activity; in vivo; indexing; inhibitor/antagonist; liquid chromatography mass spectrometry; microbial; mortality; novel; pathogen; programs; resistant strain; scaffold; soil sampling

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.

描述（由申请人提供）：真菌感染仍然是艾滋病毒感染患者发病率和死亡率的主要原因。目前，只有三类的抗真菌药适用于治疗与艾滋病相关的真菌感染，但是这些药物受到耐药性，药理限制和负面药物相互作用的阻碍。同样，通过不断变化的真菌病原体的流行病学，挑战仍然使人复杂化。必须寻找具有广泛抗真菌活性的新支架。 从天然产品中发现了抗真菌化合物。例如，在多种真菌范围内发现了葡萄糖合成抑制剂（包括pnemoncandins，其他echinocandins）。这些化合物来自在无菌条件下培养的土壤样品的发酵汤。由于复杂的环境条件对于在无菌实验室条件下产生的大多数微生物二级代谢物筛查化合物的合成至关重要，因此经常导致在这些条件下容易产生的已知化合物的重新发现。 Lifepharms，Inc。已建立了一系列田间收集的，环境挑战的水果体，目前由26,000多个基本菌和comcycetes样品（具有成果的人）组成，其中几乎包括美国大陆的所有物种。 Lifepharms的摘录库中的基本菌和comcycetes的摘录库以其独特性和化学多样性而无与伦比。 在德克萨斯大学圣安东尼奥大学（UTHSCSA）的抗真菌敏感性测试实验室和感染性疾病的划分中，我们正在筛选Lifepharms的天然产物图书馆，以防止氟康唑敏感（ATCC 90028）（ATCC 90028）和阻力型念珠菌antcce crestant antcc 90030，and 90030，686901，68552） Neoformans。 Lifepharms中的活性化合物通过单个HPLC步骤分开，并筛选出抗真菌活性和哺乳动物的毒性。那些具有活性至少两种耐药性真菌菌株的半蛋白质化合物将通过高速反电流色谱和HPLC纯化。化合物将通过NMR和LC/MS/MS方法进行解读和化学特征。麦克风将针对广泛的临床分离株确定，并将包括人类全身感染的重要原因，包括免疫能力和免疫功能强化的宿主，包括肺炎细胞。结构新颖的化合物将选择具有独特的体外抗真菌曲线的独特化合物，以进行II阶段和体内评估。 公共卫生相关性：真菌感染仍然是艾滋病毒感染患者发病和死亡率的主要原因。从天然产品中发现了抗真菌化合物。在与圣安东尼奥大学健康科学中心的抗真菌敏感性测试实验室和传染病的划分中，我们正在筛选Lifepharms的天然产品图书馆，以抗氟康唑敏感和抗性念珠菌菌株，以及烟曲霉的烟草和烟熏脂肪菌和烟草Neoformans。