Novel antifungals for Immunocompromised/HIV patients.

描述(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，但这些药物都受到耐药性、药理局限性和药物负相互作用等因素的制约。此外，由于真菌病原体流行病学的变化，这一挑战继续复杂化。寻找具有广泛抗真菌活性的新型支架势在必行。从天然产品中发现了抗真菌化合物。例如，在各种真菌中都发现了葡聚糖合成抑制剂(包括紫球菌素、其他棘球菌素)。这些化合物来自在无菌条件下培养的土壤样本的发酵液。由于复杂的环境条件对大多数微生物次级代谢物的合成至关重要，因此筛选在无菌实验室条件下产生的化合物往往会导致在这些条件下容易产生的已知化合物的重新发现。LifePharms公司已经建立了一个野外采集的、对环境构成挑战的子实体的集合，目前包括超过2.6万个担子菌和子囊菌(那些有子实体的)样本，几乎包括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的独特性和化学多样性是无与伦比的。我们与德克萨斯大学圣安东尼奥分校健康科学中心(UTHSCSA)的抗真菌敏感性测试实验室和传染病部门合作，正在筛选LifePharms的天然产品库，以对抗氟康唑敏感株(ATCC 90028)和耐药念珠菌株ATCC 90030、96901、6852以及烟曲霉和新型隐球菌。LifePharms中的活性化合物通过单一的高效液相步骤进行分离，并对其进行抗真菌活性和哺乳动物毒性筛选。那些对至少两个抗药性真菌菌株具有活性且对哺乳动物没有毒性的半纯化合物将通过高速逆流色谱和高效液相色谱分离纯化。化合物将通过核磁共振和LC/MS/MS方法进行去复制和化学表征。最低抑菌浓度将根据广泛的临床分离株进行确定，其中将包括对人类系统感染具有重要原因的物种，包括具有免疫能力和免疫功能受损的宿主，包括肺孢子虫。在第二阶段，将选择具有独特体外抗真菌特性的结构新颖的化合物进行ADMET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的主要原因。从天然产品中发现了抗真菌化合物。我们与德克萨斯大学圣安东尼奥分校健康科学中心的抗真菌敏感性测试实验室和传染病部门合作，正在筛选LifePharms的天然产物库，以对抗氟康唑敏感和耐药念珠菌菌株以及烟曲霉和新生隐球菌。

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.