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: 10043368
• 负责人: BILL J BAKER
• 金额: $ 19.46万
• 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 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10043368
• 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.

原生动物寄生虫感染给全世界人类造成严重疾病和经济损失。 最具破坏性的原生动物寄生虫感染的影响被表示为“残疾调整生命年” （世界卫生组织使用伤残调整生命年作为疾病影响的衡量标准）。 这些疾病在所有传染病中排名第二，仅次于下呼吸道疾病 感染，以及艾滋病和结核病之前。 非洲区域与这些疾病相关的沉重和不成比例的负担影响到许多人 社区，不仅导致高发病率，而且导致高水平的残疾。 其中一些疾病的性质使贫困循环永久化，给本已脆弱的人带来沉重负担 目前治疗这些疾病的药物面临着多重缺陷。 从多重耐药性到长疗程、安全性和其他副作用。 该项目的范围内，迫切需要开发具有不同治疗靶点的新药 控制疟疾、利什曼病和非洲人类锥虫病的适当功效和安全性。 该项目旨在发现用于治疗这些疾病的抗原虫天然产物药物先导物。 天然产品自古以来就被传统民族所使用，早在几十年前就处于领先地位 从20世纪到现代药学的发展，尽管经过了几十年的研究，仍有<250,000个。 考虑到已知的天然产物有 107 种，这个数字令人惊讶。 地球上存在，而其他人则认为仅真菌生物多样性就超过 106 种。 发现表观遗传调控下的沉默生物合成途径，基因编码的数量 尚未发现的天然产物肯定使已知的天然产物相形见绌。 该计划将由来自非洲药用植物的内生真菌进行研究。 该项目带来了沉默生物合成途径的培养诱导创新，以最大限度地提高筛选通量， 以及色谱技术，以减少化学型重新发现中损失的努力。 将使用具有临床意义的病原体菌株在表型测定中进行评估。 细胞毒性，那些表现出有利特征的细胞将优先考虑进行发育研究 虽然我们的目标是发现，但我们仍然致力于此提案的范围之外。 将这项工作转化为开发流程。