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者发病和死亡的主要原因。目前，适合治疗艾滋病相关真菌感染的抗真菌药物只有三类，但这些药物受到耐药性、药理学限制和药物相互作用的负面影响。此外，真菌病原体流行病学的变化使挑战继续复杂化。寻找具有广泛抗真菌活性的新支架势在必行。从天然产物中发现了抗真菌化合物。例如，在多种真菌中发现了葡聚糖合成抑制剂（包括肺念珠菌素和其他棘白菌素）。这些化合物来自在无菌条件下培养的土壤样品的发酵液。由于复杂的环境条件对大多数微生物次生代谢物的合成至关重要，筛选无菌实验室条件下产生的化合物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.已经建立了一个收集现场收集的，环境挑战的子实体的集合，目前包括超过26,000个担子菌和子囊菌（那些有子实体的）样本，几乎包括在美国大陆发现的所有物种。LifePharms从担子菌和子囊菌的子实体中提取的提取物库因其独特性和化学多样性而无与伦比。与圣安东尼奥德克萨斯大学健康科学中心（UTHSCSA）的抗真菌药敏试验实验室和传染病部合作，我们正在筛选LifePharms天然产品库对氟康唑敏感（ATCC 90028）和耐药念珠菌菌株ATCC 90030, 96901, 6852)以及烟曲霉和新生隐球菌的抗性。LifePharms'中的活性化合物通过单一HPLC步骤分离，并筛选抗真菌活性和哺乳动物毒性。对至少两种耐药真菌有活性且对哺乳动物无毒性的半纯化合物将采用高速逆流色谱和高效液相色谱进行纯化。化合物将通过核磁共振和LC/MS/MS方法进行分离和化学表征。mic将根据广泛的临床分离物确定，并将包括对人类全系统感染有重要影响的物种，包括免疫功能正常和免疫功能低下的宿主，包括肺囊虫。具有独特体外抗真菌特征的结构新颖的化合物将被选择用于ADMET和II期体内评估。