The nonartemisinin sesquiterpene lactones parthenin and parthenolide block Plasmodium falciparum sexual stage transmission

Jared N. Balaich, Derrick K. Mathias, Baldwyn Torto, Bryan T. Jackson, Dingyin Tao, Babak Ebrahimi, Brian B. Tarimo, Xavier Cheseto, Woodbridge A. Foster, Rhoel R. Dinglasan

Research output: Contribution to journalArticle

Abstract

Parthenin and parthenolide are natural products that are closely related in structure to artemisinin, which is also a sesquiterpene lactone (SQL) and one of the most important antimalarial drugs available. Parthenin, like artemisinin, has an effect on Plasmodium blood stage development. We extended the evaluation of parthenin as a potential therapeutic for the transmissible stages of Plasmodium falciparum as it transitions between human and mosquito, with the aim of gaining potential mechanistic insight into the inhibitory activity of this compound. We posited that if parthenin targets different biological pathways in the parasite, this in turn could pave the way for the development of druggable compounds that could prevent the spread of artemisininresistant parasites. We examined parthenin's effect on male gamete activation and the ookinete-to-oocyst transition in the mosquito as well as on stage V gametocytes that are present in peripheral blood. Parthenin arrested parasite development for each of the stages tested. The broad inhibitory properties of parthenin on the evaluated parasite stages may suggest different mechanisms of action between parthenin and artemisinin. Parthenin's cytotoxicity notwithstanding, its demonstrated activity in this study suggests that structurally related SQLs with a better safety profile deserve further exploration. We used our battery of assays to test parthenolide, which has a more compelling safety profile. Parthenolide demonstrated activity nearly identical to that of parthenin against P. falciparum, highlighting its potential as a possible transmission-blocking drug scaffold. We discuss the context of the evidence with respect to the next steps toward expanding the current antimalarial arsenal.

Original languageEnglish (US)
Pages (from-to)2108-2117
Number of pages10
JournalAntimicrobial Agents and Chemotherapy
Volume60
Issue number4
DOIs
StatePublished - Apr 1 2016

Fingerprint

Sesquiterpenes
Lactones
Plasmodium falciparum
Parasites
Antimalarials
Culicidae
parthenolide
parthenin
Safety
Plasmodium
Oocysts
Biological Products
Germ Cells

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Balaich, J. N., Mathias, D. K., Torto, B., Jackson, B. T., Tao, D., Ebrahimi, B., ... Dinglasan, R. R. (2016). The nonartemisinin sesquiterpene lactones parthenin and parthenolide block Plasmodium falciparum sexual stage transmission. Antimicrobial Agents and Chemotherapy, 60(4), 2108-2117. https://doi.org/10.1128/AAC.02002-15

The nonartemisinin sesquiterpene lactones parthenin and parthenolide block Plasmodium falciparum sexual stage transmission. / Balaich, Jared N.; Mathias, Derrick K.; Torto, Baldwyn; Jackson, Bryan T.; Tao, Dingyin; Ebrahimi, Babak; Tarimo, Brian B.; Cheseto, Xavier; Foster, Woodbridge A.; Dinglasan, Rhoel R.

In: Antimicrobial Agents and Chemotherapy, Vol. 60, No. 4, 01.04.2016, p. 2108-2117.

Research output: Contribution to journalArticle

Balaich, JN, Mathias, DK, Torto, B, Jackson, BT, Tao, D, Ebrahimi, B, Tarimo, BB, Cheseto, X, Foster, WA & Dinglasan, RR 2016, 'The nonartemisinin sesquiterpene lactones parthenin and parthenolide block Plasmodium falciparum sexual stage transmission', Antimicrobial Agents and Chemotherapy, vol. 60, no. 4, pp. 2108-2117. https://doi.org/10.1128/AAC.02002-15
Balaich, Jared N. ; Mathias, Derrick K. ; Torto, Baldwyn ; Jackson, Bryan T. ; Tao, Dingyin ; Ebrahimi, Babak ; Tarimo, Brian B. ; Cheseto, Xavier ; Foster, Woodbridge A. ; Dinglasan, Rhoel R. / The nonartemisinin sesquiterpene lactones parthenin and parthenolide block Plasmodium falciparum sexual stage transmission. In: Antimicrobial Agents and Chemotherapy. 2016 ; Vol. 60, No. 4. pp. 2108-2117.
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