Journal
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
Volume 70, Issue 5, Pages 1357-1366Publisher
OXFORD UNIV PRESS
DOI: 10.1093/jac/dkv003
Keywords
malaria; Plasmodium spp.; drug susceptibility testing; gametocytes; transmission; endoperoxides
Funding
- Medicines for Malaria Venture
- Bill & Melinda Gates Foundation [OPP1040394]
- Bill and Melinda Gates Foundation [OPP1040394] Funding Source: Bill and Melinda Gates Foundation
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Objectives: The development of drugs to reduce malaria transmission is an important part of malaria eradication plans. We set out to develop and validate a combination of new screening assays for prioritization of transmission-blocking molecules. Methods: We developed high-throughput assays for screening compounds against gametocytes, the parasite stages responsible for onward transmission to mosquitoes. An existing gametocyte parasitic lactate dehydrogenase (pLDH) assay was adapted for use in 384-well plates, and a novel homogeneous immunoassay to monitor the functional transition of female gametocytes into gametes was developed. A collection of 48 marketed and experimental antimalarials was screened and subsequently tested for impact on sporogony in Anopheles mosquitoes, to directly quantify the transmission-blocking properties of antimalarials in relation to their effects on gametocyte pLDH activity or gametogenesis. Results and Conclusions: The novel screening assays revealed distinct stage-specific kinetics and dynamics of drug effects. Peroxides showed the most potent transmission-blocking effects, with an intermediate speed of action and IC50 values that were 20-40-fold higher than the IC(50)s against the asexual stages causing clinical malaria. Finally, the novel synthetic peroxide OZ439 appeared to be a promising drug candidate as it exerted gametocytocidal and transmission-blocking effects at clinically relevant concentrations.
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