Coertzen, DinaReader, JanetteVan der Watt, Mariette ElizabethNondaba, SindisiweGibhard, LiezlWiesner, LubbeSmith, PeterD'Alessandro, SarahTaramelli, DonatellaWong, Ho NingDu Preez, Jan L.Wu, Ronald Wai KeungBirkholtz, Lyn-MarieHaynes, Richard K.2018-08-282018-08Coertzen D, Reader J, van der Watt M, Nondaba SH, Gibhard L, Wiesner L, Smith P, D'Alessandro S, Taramelli D, Wong HN, du Preez JL, Wu RWK, Birkholtz L-M, Haynes RK. 2018. Artemisone and artemiside are potent panreactive antimalarial agents that also synergize redox imbalance in Plasmodium falciparum transmissible gametocyte stages. Antimicrob Agents Chemother 62:e02214-17. https://doi.org/10.1128/AAC.02214-17.0066-4804 (print)1098-6596 (online)10.1128/AAC.02214-17http://hdl.handle.net/2263/66344The emergence of resistance towards artemisinin combination therapies (ACTs) by the malaria parasite Plasmodium falciparum has the potential to severely compromise malaria control. Therefore, development of new artemisinins in combination with new drugs that impart activities towards both intraerythrocytic proliferative asexual and transmissible gametocyte stages, in particular those of resistant parasites, are urgently required. We define artemisinins as oxidant drugs through their ability to oxidize reduced flavin cofactors of flavin disulfide reductases critical for maintaining redox-homeostasis in the malaria parasite. Here we compare the activities of 10-amino artemisinin derivatives towards the asexual and gametocyte stages of P. falciparum parasites. Of these, artemisone and artemiside inhibited asexual and gametocyte stages, particularly stage V gametocytes in the low nM range. Further, treatment of both early and late gametocyte stages with artemisone or artemiside combined with the pro-oxidant redox partner methylene blue displays notable synergism. These data suggest that modulation of redox-homeostasis likely is an important druggable process, particularly in gametocytes, and thereby enhances the prospect of using combinations of oxidant and redox drugs for malaria control.en© 2018 American Society for Microbiology. All Rights Reserved.Plasmodium falciparumArtemisininsParasiteGametocytesOxidative stressReactive oxygen speciesSynergismHigh-throughput assayIn vitroMethylene blueDrug sensitivityGlutathione reductase (GR)Falciparum malariaInfected erythrocytesCombination therapyPostprint Article