Induction of antiprotozoal secondary metabolites from endophytic fungi using epigenetic modifiers

原生动物寄生虫感染在世界范围内引起人类的重大疾病和经济损失。的 最具破坏性的原生动物寄生虫感染的影响以"残疾调整生命年"表示 （DIGs，世界卫生组织用来衡量疾病的影响）。遵循这些准则， 这些疾病在所有传染病中的重要性排名第二，仅次于下呼吸道疾病。 感染，艾滋病和肺结核之前。 非洲区域与这些疾病有关的沉重和不成比例的负担影响到许多人， 这不仅造成严重的发病率，而且造成严重的残疾。此外，慢性 其中一些疾病的性质使贫穷的恶性循环永久化，并使本已脆弱的 和过度紧张的医疗系统。目前针对这些疾病的处方药面临多重缺陷 从多药耐药性到长疗程、安全性和其他副作用。内 鉴于该项目的范围，迫切需要开发具有不同治疗靶点的新药， 适当的有效性和安全性，以控制疟疾、利什曼病和非洲人类锥虫病。 本项目旨在寻找治疗这些疾病的抗原虫天然产物药物先导。 天然产品自古以来就被传统民族所使用， 20世纪世纪的发展对现代药学的影响尽管经过几十年的研究， 天然产品已知这是一个令人惊讶的小数字，当一个人认为，估计有107个物种， 地球上存在的真菌，而其他人则认为真菌生物多样性超过106种。后基因组时代 在表观遗传调控下沉默的生物合成途径的发现， 尚未发现的天然产物肯定使那些已知的天然产物相形见绌。天然产物研究在此 该计划将产生从未充分研究的来源，内生真菌从非洲药用植物。我们 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， 和色谱技术，以减少化学型重新发现的努力。所有的化学多样性将是 使用具有临床意义的病原体菌株在表型测定中进行评价。点击将被评估为 细胞毒性，显示有利特征的细胞优先用于发育研究 超出了这个提议的范围。虽然我们的目标是专注于发现，但我们仍然致力于 将这项工作转化为开发管道。

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.