Induction of antiprotozoal secondary metabolites from endophytic fungi using epigenetic modifiers

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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.