Steroidal Antimetabolites Protect Mice against Trypanosoma brucei

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dc.creatorChaudhuri, Minu
dc.creatorSingha, Ujjal K.
dc.creatorVanderloop, Boden H. (TTU)
dc.creatorTripathi, Anuj
dc.creatorNes, W. David (TTU)
dc.date.accessioned2023-04-04T16:14:36Z
dc.date.available2023-04-04T16:14:36Z
dc.date.issued2022
dc.description© 2022 by the authors. Licensee MDPI, Basel, Switzerland. cc-by
dc.description.abstractTrypanosoma brucei, the causative agent for human African trypanosomiasis, is an emerging ergosterol-dependent parasite that produces chokepoint enzymes, sterol methyltransferases (SMT), not synthesized in their animal hosts that can regulate cell viability. Here, we report the lethal effects of two recently described natural product antimetabolites that disrupt Acanthamoeba sterol methylation and growth, cholesta-5,7,22,24-tetraenol (CHT) and ergosta-5,7,22,24(28)-tetrae-nol (ERGT) that can equally target T. brucei. We found that CHT/ERGT inhibited cell growth in vitro, yielding EC50 values in the low nanomolar range with washout experiments showing cidal activity against the bloodstream form, consistent with their predicted mode of suicide inhibition on SMT activity and ergosterol production. Antimetabolite treatment generated altered T. brucei cell morphology and death rapidly within hours. Notably, in vivo ERGT/CHT protected mice infected with T. brucei, doubling their survival time following daily treatment for 8–10 days at 50 mg/kg or 100 mg/kg. The current study demonstrates a new class of lead antibiotics, in the form of common fungal sterols, for antitrypanosomal drug development.
dc.identifier.citationChaudhuri, M., Singha, U.K., Vanderloop, B.H., Tripathi, A., & Nes, W.D.. 2022. Steroidal Antimetabolites Protect Mice against Trypanosoma brucei. Molecules, 27(13). https://doi.org/10.3390/molecules27134088
dc.identifier.urihttps://doi.org/10.3390/molecules27134088
dc.identifier.urihttps://hdl.handle.net/2346/92488
dc.language.isoeng
dc.subjectantimetabolite
dc.subjectcholesta-5,7,22,24-tetraenol (CHT)
dc.subjectergosta-5,7,22,24(28)-tetraenol (ERGT)
dc.subjectergosterol biosynthesis
dc.subjectsuicide substrate
dc.subjectTrypanosoma brucei
dc.titleSteroidal Antimetabolites Protect Mice against Trypanosoma brucei
dc.typeArticle

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