Induction of antiprotozoal secondary metabolites from endophytic fungi using epigenetic modifiers

使用表观遗传修饰剂从内生真菌中诱导抗原虫次级代谢产物

• 批准号: 10170264
• 负责人: BILL J BAKER
• 金额: $ 15.1万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-22 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170264
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; African; African Trypanosomiasis; Antiprotozoal Agents; Artemisinins; Biocontrols; Biodiversity; Biological; Biological Assay; Characteristics; Chemicals; Chronic; Clinical; Collection; Communicable Diseases; Communities; Development; Disease; Dose; Drug Prescriptions; Dwarfism; Economics; Epigenetic Process; Face; Florida; Fractionation; Future; Genes; Genomics; Guidelines; Health system; Human; Infection; Lead; Leishmania donovani; Leishmaniasis; Lower Respiratory Tract Infection; Malaria; Measures; Medicinal Plants; Modernization; Morbidity - disease rate; Multi-Drug Resistance; Natural Product Drug; Natural Products; Nature; Parasites; Pathway interactions; Pharmaceutical Preparations; Pharmacy facility; Phenotype; Planet Earth; Plasmodium falciparum; Poverty; Production; Protozoan Infections; Quinine; Safety; Source; Stretching; Structure; Techniques; Therapeutic; Time; Translations; Trypanosoma brucei gambiense; Tuberculosis; Universities; Work; World Health Organization; antimicrobial; base; cytotoxicity; disability; disability-adjusted life years; drug development; drug discovery; endophytic fungi; epigenetic regulation; fungus; innovation; novel; novel therapeutics; pathogen; programs; response; screening; screening program; side effect; therapeutic target

Infections with protozoan parasites cause substantial illness and economic loss in humans worldwide. The impact of infections by the most devastating protozoan parasites is expressed as “disability-adjusted life-years” (DALYs, used by the World Health Organization as a measure of disease impact). Following these guidelines, these diseases were ranked second in importance across all infectious diseases, behind lower respiratory infections, and before AIDS and tuberculosis. The heavy and disproportionate burden associated with these diseases in the African Region affects many communities, resulting not only in heavy morbidity but also in high levels of disability. In addition, the chronic nature of some of these diseases perpetuates the cycle of poverty and imposes a heavy toll on already weak and over-stretched health systems. Currently prescribed drugs for these diseases face multiple shortcomings spanning from multidrug resistance to long course of treatment, safety, and other sides effects. Within the scope of this project, there is an urgent need to develop novel drugs with different therapeutic targets and appropriate efficacy and safety profiles to control malaria, leishmaniasis, and human African trypanosomiasis. This project aims to discover antiprotozoal natural product drug leads for the treatment of these diseases. Natural products have been used by traditional peoples since time immemorial, leading in the early decades of the 20th century to the development of the modern pharmacy. Despite decades of study, there are <250,000 natural products known. This is a surprisingly small number when one considers that estimates of 107 species exist on Earth, while others suggest fungal biodiversity alone to be >106 species. Taken with post-genomic-era discovery of silent biosynthetic pathways under epigenetic regulation, the number of genetically-encoded natural products yet to be discovered surely dwarfs those already known. Natural products studied in this program will be produced from understudied sources, endophytic fungi from African medicinal plants. Our project brings innovation in culture elicitation of silent biosynthetic pathways to maximize screening throughput, and a chromatographic technique to reduce effort lost in chemotype re-discovery. All chemodiversity will be evaluated in phenotypic assays using clinically-meaningful pathogen strains. Hits will be evaluated for cytotoxicity, with those displaying favorable characteristics advancing to prioritization for developmental studies outside the scope of this proposal. While our Aims are focused on discovery, we remain committed to translation of this work into a development pipeline.

原生动物寄生虫的感染会导致全球人类的实质性疾病和经济损失。这 最毁灭性的原生动物寄生虫感染的影响表示为“残疾调整的终身年份” （达利人，世界卫生组织用作疾病影响的量度）。遵循这些准则， 这些疾病在所有传染病中排名第二，仅次于下呼吸道 感染和艾滋病和结核病之前。 非洲地区与这些疾病相关的沉重和不成比例的伯恩（Burnen）影响了许多 社区不仅出现了严重的发病率，而且导致高水平的残疾。另外，慢性 这些疾病中的某些疾病的性质使贫困的循环永存，并不可能造成沉重的损失 和超紧密的卫生系统。目前为这些疾病的处方药面临多个缺点 从多药抵抗到长期的治疗，安全性和其他方面的影响。在 该项目的范围，迫切需要开发具有不同治疗靶标的新型药物，并且 适当的效率和安全性，以控制疟疾，利什曼病和人类非洲锥虫病。 该项目旨在发现用于治疗这些疾病的抗植物天然产物药物铅。 自远古时代以来，传统人员就使用了天然产品，在几十年初期领先 20世纪的发展现代药房。尽管研究了数十年，但仍有<25万 天然产品已知。当人们认为估计107种时，这是一个令人惊讶的数字 存在于地球上，而其他人则仅认为真菌生物多样性是> 106种。与后基因组时代一起服用 在表观遗传调节下发现无声的生物合成途径，遗传编码的数量 尚未发现的天然产品肯定会识别那些已经知道的人。天然产品在此研究 计划将从可理解的来源，非洲医疗植物的内生真菌生产。我们的 项目带来了无声生物合成途径的培养引起的创新，以最大程度地提高筛查吞吐量， 以及一种色谱技术，可减少在化学型重新发现中损失的努力。所有的化学多样性将是 在表型测定中使用临床上敏感的病原体菌株评估。命中将评估 细胞毒性，那些表现出有利特征的发展方向发展为发展研究的优先次序 在此提案的范围之外。尽管我们的目标专注于发现，但我们仍然致力于 将这项工作翻译成开发管道。