A combination of new screening assays for prioritization of transmission-blocking antimalarials reveals distinct dynamics of marketed and experimental drugs

被引:43
作者
Bolscher, J. M. [1 ]
Koolen, K. M. J. [1 ]
van Gemert, G. J. [2 ]
van de Vegte-Bolmer, M. G.
Bousema, T. [2 ]
Leroy, D. [3 ]
Sauerwein, R. W. [1 ,2 ]
Dechering, K. J. [1 ]
机构
[1] TropIQ Hlth Sci, NL-6525 GA Nijmegen, Netherlands
[2] Radboud Univ Nijmegen, Med Ctr, NL-6500 HB Nijmegen, Netherlands
[3] Medicines Malaria Venture, CH-1215 Geneva 15, Switzerland
基金
比尔及梅琳达.盖茨基金会;
关键词
malaria; Plasmodium spp; drug susceptibility testing; gametocytes; transmission; endoperoxides; PLASMODIUM-FALCIPARUM GAMETOCYTES; PARASITE LACTATE-DEHYDROGENASE; SULFADOXINE-PYRIMETHAMINE; MALARIA TRANSMISSION; KENYAN CHILDREN; INFECTIVITY; GAMETOCYTOGENESIS; IDENTIFICATION; INHIBITORS; RESPONSES;
D O I
10.1093/jac/dkv003
中图分类号
R51 [传染病];
学科分类号
100401 ;
摘要
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.
引用
收藏
页码:1357 / 1366
页数:10
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