Insights into the mechanism of action of natural sesquiterpene lactones against pathogenic trypanosomatids.

Sardi, F.; Elso, O.; Fiestas, L.; Perelmuter, K.; Benítez, D; Corlatti, A.M.; Da Costa, F.; Lenz, M.; Schmidt, T.J.; Bollati-Fogolín, M.; Medeiros, A.; Sülsen, V.P.; Comini, M.A.

Abstract

Terpenoids, a diverse class of bioactive molecules found in all organisms, exhibit significant antimicrobial, antiviral, antitumor, and anti-inflammatory activities, though their mechanisms are often uncharacterized. This study investigated the anti-trypanosomatid activity and interference with intracellular thiol-redox homeostasis of seven sesquiterpene lactones from Asteraceae plants. To address this question, we used redox-reporter cell lines of Leishmania infantum promastigotes, bloodstream Trypanosoma brucei brucei, and human epithelial kidney (HEK-293). Helenalin acetate (EC50 = 0.3 μM, selectivity index = 7) and estafietin (EC50 = 6 μM, selectivity index = 3) were the most potent and selective against bloodstream T. b. brucei. All tested sesquiterpene lactones selectively induced intracellular oxidation of the redox biosensor. For example, estafietin caused redox perturbations in both trypanosomatid species but not in HEK-293 cells. Eupahakonenin B, helenalin acetate, and budlein A induced biosensor oxidation exclusively in the bloodstream T. b. brucei. Conversely, arglabin oxidized the biosensor in both trypanosomatids and HEK-293, suggesting nonspecific activity. Helenalin acetate, budlein A, and arglabin exhibited enhanced cytotoxicity against parasites with depleted low molecular weight thiols (LMWT) but did not inhibit LMWT biosynthesis and reduction. This study provides crucial insights into the cytotoxic mechanisms of sesquiterpene lactones, offering a basis for optimizing their potency and selectivity against trypanosomatids.