Cellular mechanisms of action and resistance of Plasmodium falciparum to artemisinin

• Published in: Parasitology research (1987) 2017-12, Vol.116 (12), p.3331-3339
• Main Authors: Phompradit, Papichaya, Chaijaroenkul, Wanna, Na-Bangchang, Kesara
• Format: Article
• Language: English
• Subjects: Artemisinin; Artesunate; Biomedical and Life Sciences; Biomedicine; Copy number; Detoxification; Drug resistance in microorganisms; Erythrocytes; Gene expression; Genetic aspects; Glutathione; Health aspects; Heme; Hemozoin; Immunology; Medical Microbiology; Mefloquine; Microbiology; Original Paper; Plasmodium falciparum
• ISSN: 0932-0113; 1432-1955
• DOI: 10.1007/s00436-017-5647-z

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 90 ). 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.