Abstract
Previously we have reported that the G protein-coupled receptor (GPCR)-like PfSR25 in Plasmodium falciparum is a potassium (K+) sensor linked to intracellular calcium signaling and that knockout parasites (PfSR25-) are more susceptible to oxidative stress and antimalarial compounds. Here, we explore the potential role of PfSR25 in susceptibility to the antimalarial compounds atovaquone, chloroquine, dihydroartemisinin, lumefantrine, mefloquine, piperaquine, primaquine, and pyrimethamine and the Medicine for Malaria Venture (MMV) compounds previously described to act on egress/invasion (MMV006429, MMV396715, MMV019127, MMV665874, MMV665878, MMV665785, and MMV66583) through comparative assays with PfSR25- and 3D7 parasite strains, using flow cytometry assays. The IC50 and IC90 results show that lumefantrine and piperaquine have greater activity on the PfSR25- parasite strain when compared to 3D7. For MMV compounds, we found no differences between the strains except for the compound MMV665831, which we used to investigate the store-operated calcium entry (SOCE) mechanism. The results suggest that PfSR25 may be involved in the mechanism of action of the antimalarials lumefantrine and piperaquine. Our data clearly show that MMV665831 does not affect calcium entry in parasites after we depleted their internal calcium pools with thapsigargin. The results demonstrated here shed light on new possibilities on the antimalarial mechanism, bringing evidence of the involvement of the GPCR-like PfSR25.
Highlights
Present in more than 90 countries spread across different continents, malaria is still an infectious disease with a high global impact
To understand the role of G protein-coupled receptor (GPCR)-like PfSR25 in parasite susceptibility to antimalarial compounds, we assessed the parasitemia of PfSR25- compared to the wild-type strain 3D7 relative to drugs belonging to the following classes of antimalarials: naphthoquinones, 4-aminoquinolines, endoperoxides, aryl-amino alcohols, 8-aminoquinolines, and antifolates, which are used in first-line malaria treatments
We observed a significant difference for the antimalarials lumefantrine (Figure 1) and piperaquine (Figure 2), for both the IC50 and the IC90 values in the assays comparing the knockout strain (PfSR25-) parasites with the wild-type strain (3D7)
Summary
Present in more than 90 countries spread across different continents, malaria is still an infectious disease with a high global impact. The complex biological cycle of malaria includes different microenvironments in the Anopheles mosquito vector, the liver stage and the intraerythrocytic cycle, which helps to hamper the control and eradication of the disease (Koyama et al, 2009; Da Silva et al, 2013; Schuck et al, 2013; Josling and Llinás, 2015). Another important factor that has contributed to the ineffectiveness of combating malaria is the emergence of strains resistant to the drugs used for the treatment (Khoury et al, 2020; Wicht et al, 2020). Resistance is associated with mutations in the genes for carrier proteins such as Plasmodium falciparum chloroquine resistance transporter (PfCRT) and Plasmodium falciparum multidrug resistance 1 (PfMDR1; Reed et al, 2000; Le Bras and Durand, 2003; Lee et al, 2018, Wicht et al, 2020)
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