Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 66, Issue 3, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/aac.01481-21
Keywords
cipargamin; ganaplacide; transmission-blocking activity; Plasmodium falciparum; gametocytes
Categories
Funding
- Royal Golden Jubilee Ph.D. Program [PHD/0142/2559]
- DEANMORU scholarship, Faculty of Tropical Medicine, Mahidol University
- Medical Research Council, UK
- NSTDA Thailand
- Newton Fund
- Wellcome Trust of Great Britain
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In this study, the activities of cipargamin, ganaplacide, and artesunate against artemisinin-resistant Plasmodium falciparum isolates were compared. Ganaplacide exhibited higher activities than cipargamin and artesunate, and both cipargamin and ganaplacide showed significant transmission-blocking activities against artemisinin-resistant Plasmodium falciparum.
Artemisinin resistance in Plasmodium falciparum has emerged and spread widely in the Greater Mekong Subregion, threatening current first-line artemisinin combination treatments. New antimalarial drugs are needed urgently. Cipargamin (KAE609) and ganaplacide (KAF156) are promising novel antimalarial compounds in advanced stages of development. Both compounds have potent asexual blood stage activities, inhibit P. falciparum gametocytogenesis, and reduce oocyst development in anopheline mosquitoes. In this study, we compared the asexual and sexual stage activities of cipargamin, ganaplacide, and artesunate in artemisinin-resistant P. falciparum isolates (n = 6; K13 mutations C580Y, G449A, and R539T) from Thailand and Cambodia. Asexual blood stage antimalarial activity was evaluated in a SYBR-green I-based 72-h in vitro assay, and the effects on male and female mature stage V gametocytes were assessed in the P. falciparum dual gamete formation assay. Ganaplacide had higher activities than cipargamin and artesunate, with mean (standard deviation [SD]) 50% inhibitory concentrations (IC(50)s) against asexual stages of 5.6 (1.2) nM and 6.9 (3.8) nM for male gametocytes and 47.5 (54.7) nM for female gametocytes. Cipargamin had a similar potency against male and female gametocytes, with mean (SD) IC(50)s of 115.6 (66.9) nM for male gametocytes, 104.9 (84.3) nM for female gametocytes, and 2.4 (0.7) nM for asexual stages. Both cipargamin and ganaplacide showed significant transmission-blocking activities against artemisinin-resistant P. falciparum in vitro. Artemisinin resistance in Plasmodium falciparum has emerged and spread widely in the Greater Mekong Subregion, threatening current first-line artemisinin combination treatments. New antimalarial drugs are needed urgently.
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