Cellular mechanisms of action and resistance of Plasmodium falciparum to artemisinin

Abstract

The recent reports of high failure rates and decline in in vitro sensitivity of Plasmodium falciparum to artemisinin-based combination therapies (ACTs) suggest the possibility of clinical artemisinin resistance along the Thai-Cambodian and Thai-Myanmar borders. The study investigated cellular mechanisms of action and resistance of P. falciparum to artesunate (stage specific activity, interaction with hemozoin, and anti-oxidant levels) in the two paired P. falciparum isolates (MSF046 and MSF060) collected before treatment with a 3-day artesunate-mefloquine and at the time of recrudescence. In addition, the link of these cellular mechanisms to the polymorphisms of the candidate artemisinin-resistant genes (pfatp6, pfcrt, pfmdr1, pfmrp1, and K13 propeller) was also investigated. Morphological change was observed in both pairs of the primary and recrudesced P. falciparum isolates during 12-48 h of exposure to artesunate (at IC). A marked decrease in parasite viability was found in the recrudesced isolates of both MSF046 and MSD060. The extent of the reduction (% change of baseline) in total glutathione concentrations was significantly lower in recrudesced (32.1 and 1.7%) compared with primary (45.5 and 53.7%) isolates of both MSF046 and MSF060. The extent of reduction of hemozoin content in MSF046 was significantly higher in the recrudesced (76.8%) isolate compared with the primary isolate (99.5%). For MSF060 on the other hand, increase in hemozoin content was found in the recrudesced isolate and the extent of such increase was significantly higher in recrudesced (93.1%) than the primary isolate (87.5%). Polymorphism of K13 (N458Y) together with pfmdr1 copy number correlated well with sensitivity of both isolates to artesunate. Results of this preliminary study suggests possible role of glutathione-dependent detoxification system as well as heme degradation as cellular mechanisms of action and resistance of artemisinins.

System-wide biochemical analysis reveals ozonide antimalarials initially act by disrupting Plasmodium falciparum haemoglobin digestion

“…Parasite death ultimately occurs when drug-mediated damage overwhelms these parasite defensive mechanisms. In artemisinin resistance, K13 mutations alter parasite Hb metabolism [37,63,64] and enhance antioxidant capacity [37,65,66] and stress response pathways [32], limiting the damage of drug-derived radicals and increasing parasite survival.…”

System-wide biochemical analysis reveals ozonide antimalarials initially act by disrupting Plasmodium falciparum haemoglobin digestion

“…2d), suggesting that the peroxide impact on Hb catabolism is diminished in resistant parasites. This diminished affect may be a result of increased survival of K13-mutants following short peroxide exposure and could be mediated by altered Hb metabolism [38,65,66], augmented antioxidant defence pathways [38,58,59] or an enhanced stress response [32].…”

“…Parasite death ultimately occurs when drug-mediated damage overwhelms these parasite defensive mechanisms. In artemisinin resistance, K13 mutations alter parasite Hb metabolism [38,65,66] and enhance antioxidant capacity [38,58,59] and stress response pathways [32], limiting the damage of drug-derived radicals and increasing parasite survival.…”

Resistance of <i>Plasmodium falciparum</i> to Sulfadoxine-Pyrimethamine (<i>Dhfr</i> and <i>Dhps</i>) and Artemisinin and Its Derivatives (K13): A Major Challenge for Malaria Elimination in West Africa

“…Resistance to artemisinin and its derivatives results from certain mutations in the Kelch or k13 gene located on chromosome 13 of Plasmodium falciparum [25] [26] [27]. Any mutation in the Kelch 13 gene does not systematically confer resistance to artemisinin; two main criteria validate the mutations as being associated with artemisinin resistance.…”