Abstract
Malaria is an infectious disease caused by Plasmodium group. The mechanisms of antimalarial drugs DHA/CQ are still unclear today. The inhibitory effects (IC50) of single treatments with DHA/CQ or V-ATPase inhibitor Baf-A1 or combination treatments by DHA/CQ combined with Baf-A1 on the growth of Plasmodium falciparum strain 3D7 was investigated. Intracellular cytoplasmic pH and labile iron pool (LIP) were labeled by pH probe BCECF, AM and iron probe calcein, AM, the fluorescence of the probes was measured by FCM. The effects of low doses of DHA (0.2 nM, 0.4 nM, 0.8 nM) on gene expression of V-ATPases (vapE, vapA, vapG) located in the membrane of DV were tested by RT-qPCR. DHA combined with Baf-A1 showed a synergism effect (CI = 0.524) on the parasite growth in the concentration of IC50. Intracellular pH and irons were effected significantly by different doses of DHA/Baf-A1. Intracellular pH was decreased by CQ combined with Baf-A1 in the concentration of IC50. Intracellular LIP was increased by DHA combined with Baf-A1 in the concentration of 20 IC50. The expression of gene vapA was down-regulated by all low doses of DHA (0.2/0.4/0.8 nM) significantly (p < 0.001) and the expression of vapG/vapE were up-regulated by 0.8 nM DHA significantly (p < 0.001). Interacting with ferrous irons, affecting the DV membrane proton pumping and acidic pH or cytoplasmic irons homeostasis may be the antimalarial mechanism of DHA while CQ showed an effect on cytoplasmic pH of parasite in vitro. Lastly, this article provides us preliminary results and a new idea for antimalarial drugs combination and new potential antimalarial combination therapies.
Highlights
Malaria is a mosquito-borne infectious disease affecting humans and other animals caused by single-celled microorganisms belonging to the Plasmodium group
DHA combined with Bafilomycin A1 (Baf-A1) at a concentration of IC50 showed synergism effect (CI = 0.524), while CQ combined with Baf-A1 showed only antagonism effect or nearly additive effect (CI = 1.012) in all groups
We provide evidence for antimalarial drug combinations, which DHA combined with Baf-A1 in a concentration of
Summary
Malaria is a mosquito-borne infectious disease affecting humans and other animals caused by single-celled microorganisms belonging to the Plasmodium group. There were estimated 219 million clinical cases of malaria and 435,000 deaths from malaria globally in 2017. Plasmodium falciparum (P. f ) is the most prevalent malaria parasite in most of the WHO Regions [1]. Health Organization’s List of Essential Medicines, has long been used in the treatment or prevention of malaria, while P. falciparum has developed widespread resistance to it. Artemisinins (ARTs) in combination with other antimalarial drugs (artemisinin-combination therapies/ACTs) have been integral to the recent success of global malaria control, especially for P. falciparum.
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