Comparison of the exposure time dependence of the activities of synthetic ozonide antimalarials and dihydroartemisinin against K13 wild-type and mutant Plasmodium falciparum strains

Tuo Yang, Stanley C. Xie, Pengxing Cao, Carlo Giannangelo, James McCaw, Darren J Creek, Susan A Charman, Nectarios Klonis, Leann Tilley

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Fully synthetic endoperoxide antimalarials, namely, OZ277 (RBx11160; also known as arterolane) and OZ439 (artefenomel), have been approved for marketing or are currently in clinical development. We undertook an analysis of the kinetics of the in vitro responses of Plasmodium falciparum to the new ozonide antimalarials. For these studies we used a K13 mutant (artemisinin resistant) isolate from a region in Cambodia and a genetically matched (artemisinin sensitive) K13 revertant. We used a pulsed-exposure assay format to interrogate the time dependence of the response. Because the ozonides have physicochemical properties different from those of the artemisinins, assay optimization was required to ensure that the drugs were completely removed following the pulsed exposure. Like that of artemisinins, ozonide activity requires active hemoglobin degradation. Short pulses of the ozonides were less effective than short pulses of dihydroartemisinin; however, when early-ring-stage parasites were exposed to drugs for periods relevant to their in vivo exposure, the ozonide antimalarials were markedly more effective.

Original languageEnglish
Pages (from-to)4501-4510
Number of pages10
JournalAntimicrobial Agents and Chemotherapy
Volume60
Issue number8
DOIs
Publication statusPublished - 1 Aug 2016

Cite this

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title = "Comparison of the exposure time dependence of the activities of synthetic ozonide antimalarials and dihydroartemisinin against K13 wild-type and mutant Plasmodium falciparum strains",
abstract = "Fully synthetic endoperoxide antimalarials, namely, OZ277 (RBx11160; also known as arterolane) and OZ439 (artefenomel), have been approved for marketing or are currently in clinical development. We undertook an analysis of the kinetics of the in vitro responses of Plasmodium falciparum to the new ozonide antimalarials. For these studies we used a K13 mutant (artemisinin resistant) isolate from a region in Cambodia and a genetically matched (artemisinin sensitive) K13 revertant. We used a pulsed-exposure assay format to interrogate the time dependence of the response. Because the ozonides have physicochemical properties different from those of the artemisinins, assay optimization was required to ensure that the drugs were completely removed following the pulsed exposure. Like that of artemisinins, ozonide activity requires active hemoglobin degradation. Short pulses of the ozonides were less effective than short pulses of dihydroartemisinin; however, when early-ring-stage parasites were exposed to drugs for periods relevant to their in vivo exposure, the ozonide antimalarials were markedly more effective.",
author = "Tuo Yang and Xie, {Stanley C.} and Pengxing Cao and Carlo Giannangelo and James McCaw and Creek, {Darren J} and Charman, {Susan A} and Nectarios Klonis and Leann Tilley",
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Comparison of the exposure time dependence of the activities of synthetic ozonide antimalarials and dihydroartemisinin against K13 wild-type and mutant Plasmodium falciparum strains. / Yang, Tuo; Xie, Stanley C.; Cao, Pengxing; Giannangelo, Carlo; McCaw, James; Creek, Darren J; Charman, Susan A; Klonis, Nectarios; Tilley, Leann.

In: Antimicrobial Agents and Chemotherapy, Vol. 60, No. 8, 01.08.2016, p. 4501-4510.

Research output: Contribution to journalArticleResearchpeer-review

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