Identification of Leucinostatins from Ophiocordyceps sp. as Antiparasitic Agents against Trypanosoma cruzi .
Jean A BernatchezYun-Seo KilElany Barbosa da SilvaDiane ThomasLaura-Isobel McCallKaren L WendtJulia M SouzaJasmin AckermannJames H McKerrowRobert H CichewiczJair Lage Siqueira-NetoPublished in: ACS omega (2022)
Safe and effective treatments for Chagas disease, a potentially fatal parasitic infection associated with cardiac and gastrointestinal pathology and caused by the kinetoplastid parasite Trypanosoma cruzi , have yet to be developed. Benznidazole and nifurtimox, which are currently the only available drugs against T. cruzi , are associated with severe adverse effects and questionable efficacy in the late stage of the disease. Natural products have proven to be a rich source of new chemotypes for other infectious agents. We utilized a microscopy-based high-throughput phenotypic screen to identify inhibitors of T. cruzi from a library of natural product samples obtained from fungi procured through a Citizen Science Soil Collection Program (https://whatsinyourbackyard.org/) and the Great Lakes (USA) benthic environment. We identified five leucinostatins (A, B, F, NPDG C, and NPDG D) as potent inhibitors of the intracellular amastigote form of T. cruzi . Leucinostatin B also showed in vivo suppression of T. cruzi in a mouse model of Chagas disease. Given prior reports that leucinostatins A and B have antiparasitic activity against the related kinetoplastid Trypanosoma brucei , our findings suggest a potential cross-trypanocidal compound class and provide a platform for the further chemical derivatization of a potent chemical scaffold against T. cruzi .
Keyphrases
- trypanosoma cruzi
- high throughput
- mouse model
- ms ms
- heart failure
- high resolution
- drug induced
- liquid chromatography tandem mass spectrometry
- high performance liquid chromatography
- emergency department
- risk assessment
- atrial fibrillation
- mass spectrometry
- simultaneous determination
- anti inflammatory
- high speed
- tissue engineering