Antimalarial Iron Chelator FBS0701 Blocks Transmission by Plasmodium falciparum Gametocyte Activation Inhibition

Abstract

Reducing the transmission of the malarial parasite by Anopheles mosquitoes using drugs or vaccines remains a main focus in the efforts to control malaria. Iron chelators have been studied as potential antimalarial drugs due to their activities against different stages of the parasite. The iron chelator FBS0701 affects the development of Plasmodium falciparum early gametocytes and lowers blood-stage parasitemia. Here, we tested the effect of FBS0701 on stage V gametocyte infectivity for mosquitoes. The incubation of stage V gametocytes for up to 3 days with increasing concentrations of FBS0701 resulted in a significant dose-related reduction in mosquito infectivity, as measured by the numbers of oocysts per mosquito. The reduction in mosquito infectivity was due to the inhibition of male and female gametocyte activation. The preincubation of FBS0701 with ferric chloride restored gametocyte infectivity, showing that the inhibitory effect of FBS0701 was quenched by iron. Deferoxamine, another iron chelator, also reduced gametocyte infectivity but to a lesser extent. Finally, the simultaneous administration of drug and gametocytes to mosquitoes without previous incubation did not significantly reduce the numbers of oocysts. These results show the importance of gametocyte iron metabolism as a potential target for new transmission-blocking strategies.

Natural Phenolic Compounds and Derivatives as Potential Antimalarial Agents

“…The way flavonoids might interfere with heme is not entirely clarified, since their acidic nature, although weak, might prevent their entry in the digestive vacuole, where the heme is [4]. Flavonoids are demonstrated radical scavengers that bind easily with metals, specially iron, and are able to form stable complexes with Fe (II), therefore preventing it from partaking in other reactions, such as DNA synthesis and energy-enzymatic pathways, possibly starving the parasite [4,54,74,76,78]. Theoretically, and similarly to synthetic iron chelators that have been studied toward P. falciparum, flavo-noids might also interfere with mosquito transmission [78].…”

“…Flavonoids are demonstrated radical scavengers that bind easily with metals, specially iron, and are able to form stable complexes with Fe (II), therefore preventing it from partaking in other reactions, such as DNA synthesis and energy-enzymatic pathways, possibly starving the parasite [4,54,74,76,78]. Theoretically, and similarly to synthetic iron chelators that have been studied toward P. falciparum, flavo-noids might also interfere with mosquito transmission [78]. Since iron is a key-component in the function of the gametocyteʼs mitochondrial electron transport chain, chelation is thought to inhibit this system, thus inactivating the gametocyte [78].…”

“…Theoretically, and similarly to synthetic iron chelators that have been studied toward P. falciparum, flavo-noids might also interfere with mosquito transmission [78]. Since iron is a key-component in the function of the gametocyteʼs mitochondrial electron transport chain, chelation is thought to inhibit this system, thus inactivating the gametocyte [78]. Transmission tests with flavonoids would have to be performed to confirm this.…”

A Systematic Analysis of Mosquito-Microbiome Biosynthetic Gene Clusters Reveals Antimalarial Siderophores that Reduce Mosquito Reproduction Capacity

“…Activity against Plasmodium gametocyte or mosquito stages is an especially attractive activity for candidate small molecules to reduce malaria transmission. Importantly, iron chelators including FBS0701 and deferoxamine, have been shown to inhibit gametocyte development (Ferrer et al, 2015). This suggests that other compounds that reduce iron levels, like siderophores, have potential to block the transmission of malaria.…”

Prophylaxis with Artemisia annua is Very Efficient: The Role of Chelators

“…It requires several days of administration. This appears logical and recommendable as the gametocytogenesis and gametocyte circulation spread over several weeks after the asexual stage [39]. In fact the efficiency of these chelators is known since 25 years [40].…”