Phyloactivity-based screening of ethnomedically inspired plant extract libraries against Trypanosoma cruzi and Chagas disease

Trypanosoma cruzi is the etiologic agent of Chagas’ disease, a neglected tropical disease prevalent in America. Chemotherapy with benznidazole or nifurtimox is effective when administered in the acute stage but the efficacy rapidly decreases in the chronic phase and these drugs become toxic [1]. Intervention with botanical drugs seems to be a possible alternative against parasitic diseases, especially among rural communities where triatomine bugs still infect people [2]. However, a systematic analysis to challenge this hypothesis is lacking. We performed a one-year ethnobotanical/pharmacological fieldwork among indigenous groups in the Bolivian Chaco where the Chagas disease is hyperendemic. Our hypothesis was that ethnopharmacologically inspired plant extract libraries show a higher degree of specific antitrypanosomal activities than a comprehensive Dioscoroides medicinal plant extract library without association to trypanosomiasis. To that aim, we have established a BSL3* lab in Bern to assess selective toxicity towards the different stages of the parasite during host infection and in comparison, with T. brucei and mammalian host cells. So far, more than 750 plant taxa were assessed. Few plants have been subjected to bioactivity-guided isolation using LC-MS and structure elucidation. Based on our most active clusters we found naphthalene, sesquiterpene lactones and anthraquinones. A library of 20 anthraquinones was tested. Some of the anthraquinone derivatives showed nM potencies in the infection assay but did not exhibit antitrypanosomal activity on the insect stage, indicating a stage-dependent mechanism of action specific to the host-parasite interaction. We will present a phyloactivity-based screening including activity-based protein profiling and LC-MS/MS on parasite and host biochemistry.

• References

• 1 Anis Rassi Jr. Anis Rassi JAM-N, Lancet. Chagas disease. Lancet 2018; 391: 82-94 .
• 2 Salm A, Gertsch J. Cultural perception of triatomine bugs and Chagas disease in Bolivia: A cross-sectional field study, Parasites & Vectors. 2019 in press.