Induction of antiprotozoal secondary metabolites from endophytic fungi using epigenetic modifiers

感染原生动物寄生虫会在世界各地的人类中造成重大疾病和经济损失。这个 最具破坏性的原生动物寄生虫感染的影响以“残疾调整寿命年”表示。 (DALYs，世界卫生组织用来衡量疾病影响的指标)。遵循这些指导方针， 在所有传染病中，这些疾病的重要性排在第二位，仅次于下呼吸道 感染，以及艾滋病和结核病之前。 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 这不仅导致严重的发病率，而且还导致高水平的残疾。此外，慢性病 其中一些疾病的性质使贫困的循环永久化，并对本已脆弱的人造成沉重的损失 以及不堪重负的医疗体系。目前治疗这些疾病的处方药面临着多重缺陷 从多药耐药到长疗程、安全性和其他副作用。在 这个项目的范围，迫切需要开发具有不同治疗靶点的新药和 控制疟疾、利什曼病和人类非洲锥虫病的适当有效性和安全性概况。 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。 天然产品自古以来就被传统民族使用，早在最初的几十年就开始使用。 20世纪到现代药学的发展。尽管经过了几十年的研究，但仍有25万英镑 已知的天然产品。考虑到107个物种的估计，这是一个令人惊讶的小数字 存在于地球上，而另一些人则认为仅真菌生物多样性就有106种。后基因组时代的照片 表观遗传调控下沉默生物合成途径的发现 尚未发现的天然产品肯定会让已知的产品相形见绌。本研究所研究的天然产物 该计划将从未得到充分研究的非洲药用植物内生真菌来源中产生。我们的 该项目带来了无声生物合成途径的培养激发方面的创新，以最大限度地提高筛选吞吐量， 以及一种减少化学型重新发现过程中损失的努力的层析技术。所有的化学多样性将是 在表型分析中使用具有临床意义的病原体菌株进行评估。将对命中率进行评估 细胞毒性，那些表现出良好特征的人进入发育研究的优先顺序 不在这项提议的范围之内。虽然我们的目标是发现，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.