Targeting the gametocyte to block malaria transmission

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	NIAID	INFECTDIS-14

Authors

• TQ Tanaka
• WA Guiguemde
• RK Guy
• KC Williamson

Abstract

Malaria transmission requires the formation of mature Plasmodium gametocytes that can initiate sporogonic development once taken up by a mosquito. Although the resistance of late stage gametocytes to most standard anti-malaria drugs has been reported, the identification of additional gametocytocidal drugs has been limited by the low yield of in vitro gametocyte cultures and the lack of a standardized assay for gametocyte viability other than Giemsa-staining. Therefore, fluorescent oxidoreduction indicator alamarBlue was used to develop a screen for gametocyte viability in a 96-well format. The signal increases linearly with gametocyte number R2=0.99 and determination of the IC50 of epoxomicin demonstrated the assay was reproducible and sensitive (IC50 2.16±0.57nM, Z'-factor 0.81±0.01). Eight anti-malarials, including cycloguanil, were tested and at 10μM only primaquine, dihydroartemisinin and proguanil decreased gametocyte viability. Interestingly, proguanil, the prodrug of cycloguanil, had an IC50 of 2.2μM, which is within the therapeutic range, suggesting it could be further developed as a transmission blocking drug. An additional screen of 260 compounds that block asexual growth at 2µM only identified six compounds that decreased gametocyte viability more than 50%. These findings clearly illustrate the importance of direct gametocytocidal screening to identify drugs that block malaria transmission.

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