Abstract
Artemisinin resistance is a major threat to malaria control efforts. Resistance is characterized by an increase in the Plasmodium falciparum parasite clearance half-life following treatment with artemisinin-based combination therapies (ACTs) and an increase in the percentage of surviving parasites. The remarkably short blood half-life of artemisinin derivatives may contribute to drug-resistance, possibly through factors including sub-lethal plasma concentrations and inadequate exposure. Here we selected for a new strain of artemisinin resistant parasites, termed the artemisinin resistant strain 1 (ARS1), by treating P. falciparum Palo Alto (PA) cultures with sub-lethal concentrations of dihydroartemisinin (DHA). The resistance phenotype was maintained for over 1 year through monthly maintenance treatments with low doses of 2.5 nM DHA. There was a moderate increase in the DHA IC50 in ARS1 when compared with parental strain PA after 72 h of drug exposure (from 0.68 nM to 2 nM DHA). In addition, ARS1 survived treatment physiologically relevant DHA concentrations (700 nM) observed in patients. Furthermore, we confirmed a lack of cross-resistance against a panel of antimalarials commonly used as partner drugs in ACTs. Finally, ARS1 did not contain Pfk13 propeller domain mutations associated with ART resistance in the Greater Mekong Region. With a stable growth rate, ARS1 represents a valuable tool for the development of new antimalarial compounds and studies to further elucidate the mechanisms of ART resistance.
Highlights
Plasmodium falciparum is the most lethal of the malaria known to infect humans [1], and was responsible for nearly 212 million new cases and 429.000 deaths in 2016 [2]
We present a novel P. falciparum artemisinin resistant strain (ARS1) that possess a high tolerance against sub-lethal DHA concentrations and this
We first performed experiments to select for artemisinin resistant parasites by experimentally determining the lowest concentration of DHA that would enable continuous culture of P. falciparum strains Palo Alto (PA), FCR3 and H3BA when subjected to intermittent sub-lethal drug exposure
Summary
Plasmodium falciparum is the most lethal of the malaria known to infect humans [1], and was responsible for nearly 212 million new cases and 429.000 deaths in 2016 [2]. Derived from the plant Artemisia annua, ART contain an endoperoxide ring essential for its potent and rapid antimalarial activity [3, 4]. Ring-stage parasites are most sensitive to drug treatment, ART. A new in vitro model of P. falciparum are active against all asexual stages of parasite development [5]. The use of ART as mono-therapies has contributed to the increase and spread of artemisinin resistant parasites, and remains a major threat for malaria control efforts in South East Asia [6]. Artemisinin derivatives are only used in combination with slow-acting partner drugs as ACTs to deter drug—resistance, resistance to partner drugs has been detected [7, 8], further necessitating the development of new and effective antimalarials [9, 10]
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