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J Antimicrob Chemother. 2015 May;70(5):1357-66. doi: 10.1093/jac/dkv003. Epub 2015 Feb 8.

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

Author information

1
TropIQ Health Sciences, Geert Grooteplein 28, huispost 268, 6525 GA, Nijmegen, The Netherlands.
2
Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
3
Medicines for Malaria Venture, Route de Pré-Bois 20, 1215 Geneva 15, Switzerland.
4
TropIQ Health Sciences, Geert Grooteplein 28, huispost 268, 6525 GA, Nijmegen, The Netherlands Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
5
TropIQ Health Sciences, Geert Grooteplein 28, huispost 268, 6525 GA, Nijmegen, The Netherlands k.dechering@tropiq.nl.

Abstract

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 IC50s 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.

KEYWORDS:

Plasmodium spp.; drug susceptibility testing; endoperoxides; gametocytes; malaria; transmission

PMID:
25667405
DOI:
10.1093/jac/dkv003
[Indexed for MEDLINE]

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