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.
