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

来源：

JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY | 2015年 / 70卷 / 05期

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

页码：1357 / 1366

页数：10