Abstract
BackgroundMalaria transmission depends on infected mosquitoes and can be controlled by transmission-blocking drugs. The recently discovered FREP1-mediated malaria transmission pathway is an excellent target to screen drugs for limiting transmission.MethodsTo identify candidate small molecules, we used an ELISA-based approach to analyze extracts from a fungal library for inhibition of the FREP1–parasite interaction. We isolated and determined one active compound by chromatography and crystallography, respectively. We measured the effects of the bioactive compound on malaria transmission to mosquitoes through standard membrane-feeding assays (SMFA) and on parasite proliferation in blood by culturing.ResultsWe discovered the ethyl acetate extract of the fungus Purpureocillium lilacinum that inhibited Plasmodium falciparum transmission to mosquitoes. Pre-exposure to the extract rendered Anopheles gambiae resistant to Plasmodium infection. Furthermore, we isolated one novel active compound from the extract and identified it as 3-amino-7,9-dihydroxy-1-methyl-6H-benzo[c]chromen-6-one, or “pulixin.” Pulixin prevented FREP1 from binding to P. falciparum-infected cell lysate. Pulixin blocked the transmission of the parasite to mosquitoes with an EC50 (the concentration that gave half-maximal response) of 11 µM based on SMFA. Notably, pulixin also inhibited the proliferation of asexual-stage P. falciparum with an EC50 of 47 nM. The compound did not show cytotoxic effects at a concentration of 116 µM or lower.ConclusionBy targeting the FREP1–Plasmodium interaction, we discovered that Purpureocillium lilacinum extract blocked malaria transmission. We isolated and identified the bioactive agent pulixin as a new compound capable of stopping malaria transmission to mosquitoes and inhibiting parasite proliferation in blood culture.Graphical
Highlights
Malaria transmission depends on infected mosquitoes and can be controlled by transmission-blocking drugs
The extracts that inhibited 90% of the fibrinogen-related protein 1 (FREP1)– parasite interaction were further analyzed for their activity in blocking malaria transmission with standard membrane-feeding assays (SMFA) [18]
We focused on one fungal extract, global fungal extract library (GFEL)-12E6 (GFEL plate 12, row E, column 6), because it completely inhibited transmission of P. falciparum to An. gambiae at 1 μg/mL and was more active than the other candidates
Summary
Malaria transmission depends on infected mosquitoes and can be controlled by transmission-blocking drugs. FREP1 binds to parasites in the mosquito midgut and mediates Plasmodium invasion [11, 12]. Since mosquito FREP1 facilitates Plasmodium infection through direct binding to gametocytes and ookinetes [12], small molecules that interrupt this interaction should be ideal candidates to block malaria transmission [17, 18]. Such compounds can be administered to malaria patients or be sprayed outdoors, indoors, or on bed nets. Very few preparations are available in the market for this purpose [19]
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