Project summary
The intestinal protozoan pathogen Giardia lamblia causes considerable morbidity and mortality on a global scale.
This parasite inflicts a disproportionate burden on the young, especially in resource limited countries.
Furthermore, treatment options are limited, and drug resistance is building, setting the stage for even greater
human suffering due to infections caused by G. lamblia. Unfortunately, there is currently little hope to reverse
this impending threat due to a lack of effective drugs in the drug development pipelines. Our team will address
this urgent need through the establishment of a robust natural-products-focused testing initiative aimed at the
identification and development of new chemical matter capable of controlling these intestinal protozoan
pathogens. The proposed research takes steps toward realizing the goal of developing new antiparasitic
therapeutics for treating G. lamblia infections through a systematic approach outlined in our three research aims:
1) Investigate a library of crude fungi extracts for selective inhibitors of G. lamblia, 2) Use bioassay-guided
fractionation to purify bioactive chemical constituents of crude fungal extracts that have antigiardia activities, and
3) Evaluate the biological activities of the purified compounds against G. lamblia trophozoites to determine in
vitro and in vivo activity profiles. Such efforts would have a significant benefit to those infected or at risk of
infection by G. lamblia as new therapeutic options are desperately needed, especially for those living in resource-
poor regions where the moderate-to-severe diarrhea caused by infections leads to stunted growth, neurological
defects, malnourishment, and death. Our approach will focus on the application of natural products derived from
biologically diverse fungi, which is an underutilized resource as it applies to infections caused by intestinal
protozoans. A combination of pre-purified natural products and extracts from a large citizen-science-centered
fungal collection will provide thousands of samples needed for bioassay investigations. Bioassay-guided
purification processes coupled with advanced LC-MS dereplication strategies, MS, NMR, and other
spectroscopic tools will be used to propel studies of the fungal-derived compounds toward the identification of
promising therapeutic scaffolds. The early incorporation of in vivo mouse models of PK and efficacy will serve to
greatly accelerate the investigative process to reveal promising bioactive chemical matter, which will become
the subjects of further biological and early-stage preclinical investigations. Our team, which brings together
expertise in neglected infectious diseases drug development (University of Washington) and natural products
chemistry (University of Oklahoma), offers an exciting opportunity to uncover new therapeutic leads that will
become the subjects of future, focused development efforts aimed at providing the drugs needed to protect those
at risk of suffering from these debilitating and deadly parasitic infections.