Similarly Efficacious Anti-Malarial Drugs SJ733 and Pyronaridine Differ in Their Ability to Remove Circulating Parasites in Mice
BACKGROUND: Artemisinin-based combination therapy (ACT) has been a mainstay for malaria prevention and treatment. However, emergence of drug resistance has incentivised development of new drugs. Defining the kinetics with which circulating parasitized red blood cells (pRBC) are lost after drug treatment, referred to as the "parasite clearance curve", has been critical for assessing drug efficacy; yet underlying mechanisms remain partly unresolved. The clearance curve may be shaped both by the rate at which drugs kill parasites, and the rate at which drug-affected parasites are removed from circulation.
METHODS: In this context, two anti-malarials, SJ733, and an ACT partner drug, pyronaridine were compared against sodium artesunate in mice infected with Plasmodium berghei (strain ANKA). To measure each compound's capacity for pRBC removal in vivo, flow cytometric monitoring of a single cohort of fluorescently-labelled pRBC was employed, and combined with ex vivo parasite culture to assess parasite maturation and replication.
RESULTS: These three compounds were found to be similarly efficacious in controlling established infection by reducing overall parasitaemia. While sodium artesunate acted relatively consistently across the life-stages, single-dose SJ733 elicited a biphasic effect, triggering rapid, partly phagocyte-dependent removal of trophozoites and schizonts, followed by arrest of residual ring-stages. In contrast, pyronaridine abrogated maturation of younger parasites, with less pronounced effects on mature parasites, while modestly increasing pRBC removal.
CONCLUSIONS: Anti-malarials SJ733 and pyronaridine, though similarly efficacious in reducing overall parasitaemia in mice, differed markedly in their capacity to arrest replication and remove pRBC from circulation. Thus, similar parasite clearance curves can result for anti-malarials with distinct capacities to inhibit, kill and clear parasites.
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This work was supported by the Australian Research Council (Grant DP120100064), the National Health and Medical Research Council (NH&MRC), Australia [Grants 1082022 (to MPD, DC, AH), 1080001 (to MPD), 1028634 (to AH), 1028641 (to AH), 1126399 (to AH) and 1141921 (to DSK)], and the Australian Centre for Immunotherapy and Vaccine Development. The University of New South Wales provided the International Postgraduate Research Scholarship to RA. The authors are grateful to J. Moehrle at Medicines for Malaria Venture for providing sodium artesunate.
All data will be made available upon reasonable request.
SheelaNair, Arya; Romanczuk, Aleksandra S.; Aogo, Rosemary A.; Haldar, Rohit Nemai; Lansink, Lianne I. M.; Cromer, Deborah; Salinas, Yandira G.; Guy, R. Kiplin; McCarthy, James S.; Davenport, Miles P.; Haque, Ashraful; and Khoury, David S., "Similarly Efficacious Anti-Malarial Drugs SJ733 and Pyronaridine Differ in Their Ability to Remove Circulating Parasites in Mice" (2022). Pharmaceutical Sciences Faculty Publications. 205.
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Published in Malaria Journal, v. 21, article no. 49.
© 2022 The Author(s)
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