Wednesday, April 2, 2025
4/2/2025
Discovery of fungus-derived natural products as new and effective Antigiardial agents. - 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.
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