Journal of global antimicrobial resistance · 2025
Elucidating artemisinin (ART)-heme as a biomarker for ART resistance and ATP-dependent transport of ART in Plasmodium falciparum.
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Liu Hui, Zhou Hongchang, Cai Yuan, Du Shanshan, Huang Zhenghui, Xu Kun, Xing Jie
Аннотация
OBJECTIVES: Artemisinin (ART) resistance is widespread in Southeast Asia and emerging in Africa. In this study, the potential biomarker for ART resistance was first characterised in P. falciparum, and the roles of several molecular pathways (e.g., Hb endocytosis) in ART resistance were then evaluated.
METHODS: The metabolic profiles of ART and its pharmacokinetics were studied in Plasmodium falciparum (P. falciparum) incubated in vitro. Several strains of P. falciparum (ART-sensitive strains Pf3D7/PfDd2, and ART-resistance strain Pf6320 carrying K13 mutation C580Y) synchronised at different stages (ring and trophozoite) were used. The antimalarial activity of ART-heme adduct was evaluated. Several molecular pathways (i.e., Hb endocytosis) were evaluated for their roles in ART resistance using (non)selective inhibitors.
RESULTS: ART-heme adduct was identified as a major metabolite for ART in P. falciparum, and it exhibited weak antimalarial activity (µM level). In ART-sensitive parasites, the formation of ART-heme was rapid, and both time- and concentration-dependent (50-450 nM). In contrast, ART-heme formation in ART-resistant parasites was independent of ART concentration. ART-heme formation was susceptible to orthovanadate (an inhibitor of P-type ATPase). Hb endocytosis/degradation, SERCA and the efflux transporter played roles in ART-heme formation to some extent. Synergistic antiplasmodial effect existed between ART and verapamil (an inhibitor of the efflux transporter).
CONCLUSIONS: ART-heme adduct displayed weak antiplasmodial activity but may still serve as a biomarker for both the antiplasmodial efficacy of ART and its resistance. ART transport in P. falciparum was ATP-dependent, and inhibition of efflux transporter may be a strategy to enhance ART potency.
METHODS: The metabolic profiles of ART and its pharmacokinetics were studied in Plasmodium falciparum (P. falciparum) incubated in vitro. Several strains of P. falciparum (ART-sensitive strains Pf3D7/PfDd2, and ART-resistance strain Pf6320 carrying K13 mutation C580Y) synchronised at different stages (ring and trophozoite) were used. The antimalarial activity of ART-heme adduct was evaluated. Several molecular pathways (i.e., Hb endocytosis) were evaluated for their roles in ART resistance using (non)selective inhibitors.
RESULTS: ART-heme adduct was identified as a major metabolite for ART in P. falciparum, and it exhibited weak antimalarial activity (µM level). In ART-sensitive parasites, the formation of ART-heme was rapid, and both time- and concentration-dependent (50-450 nM). In contrast, ART-heme formation in ART-resistant parasites was independent of ART concentration. ART-heme formation was susceptible to orthovanadate (an inhibitor of P-type ATPase). Hb endocytosis/degradation, SERCA and the efflux transporter played roles in ART-heme formation to some extent. Synergistic antiplasmodial effect existed between ART and verapamil (an inhibitor of the efflux transporter).
CONCLUSIONS: ART-heme adduct displayed weak antiplasmodial activity but may still serve as a biomarker for both the antiplasmodial efficacy of ART and its resistance. ART transport in P. falciparum was ATP-dependent, and inhibition of efflux transporter may be a strategy to enhance ART potency.