Abstract
Treatment of the symptomatic asexual stage of Plasmodium falciparum relies almost exclusively on artemisinin (ART) combination therapies (ACTs) in endemic regions. ACTs combine ART or its derivative with a long-acting partner drug to maximize efficacy during the typical three-day regimen. Both laboratory and clinical studies have previously demonstrated that the common drug resistance determinants P. falciparum chloroquine resistance transporter (PfCRT) and multidrug resistance transporter (PfMDR1) can modulate the susceptibility to many current antimalarial drugs and chemical compounds. Here we investigated the parasite responses to dihydroartemisinin (DHA) and various Ca2+ and Na+ channel blockers and showed positively correlated responses between DHA and several channel blockers, suggesting potential shared transport pathways or mode of action. Additionally, we demonstrated that PfCRT and PfMDR1 could also significantly modulate the pharmacodynamic interactions of the compounds and that the interactions were influenced by the parasite genetic backgrounds. These results provide important information for better understanding of drug resistance and for assessing the overall impact of drug resistance markers on parasite response to ACTs.
Highlights
Treatment of the symptomatic asexual stage of Plasmodium falciparum relies almost exclusively on artemisinin (ART) combination therapies (ACTs) in endemic regions
It is possible that the differences in IC50 values represent background genetic variations that may support the emergence of higher delayed parasite clearance (DPC) phenotype, including drug transporters such as the P. falciparum chloroquine resistance transporter (PfCRT) and PfMDR1 that are known to transport drugs across the parasite digestive vacuole (DV) membrane[22,23,24]
Our results were based on IC50 measurements that were different from those of DPC or the Ring-stage Survival Assays (RSA)[32], our study provides important information on how parasite genetic background affects drug transport and metabolism, and may affect DPC/RSA among parasites with the same or similar K13 mutations
Summary
Treatment of the symptomatic asexual stage of Plasmodium falciparum relies almost exclusively on artemisinin (ART) combination therapies (ACTs) in endemic regions. ACTs combine ART or its derivative with a long-acting partner drug to maximize efficacy during the typical three-day regimen Both laboratory and clinical studies have previously demonstrated that the common drug resistance determinants P. falciparum chloroquine resistance transporter (PfCRT) and multidrug resistance transporter (PfMDR1) can modulate the susceptibility to many current antimalarial drugs and chemical compounds. Chemical screenings have been employed to predict functional and regulatory divergence of PfCRT25 and to show that small molecules associated with similar transcriptional responses had similar chemical features and/or mode of action (MOA)[30] Another approach to study genes associated with drug resistance is to pressure parasites to become resistant to a drug and sequence the genomes of the sensitive wild type and resistant mutant parasites to detect mutation(s) that are likely to play a role in the resistance phenotype[31]
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