Antimalarial drug sulfadoxine induces gametocytogenesis in Plasmodium berghei.

BACKGROUND: The spread of antimalarial drug resistance parasites is a major obstacle in eliminating malaria in endemic areas. This increases the urgency for developing novel antimalarial drugs with improved profiles to eliminate both sensitive and resistant parasites in populations. The invention of the drug candidates needs a model for sensitive and resistant parasites on a laboratory scale. METHODS: Repeated Incomplete Treatment (RIcT) method was followed in raising the rodent malaria parasite, Plasmodium berghei, resistant to sulfadoxine. Plasmodium berghei were exposed to an adequate therapeutic dose of sulfadoxine without finishing the treatment to let the parasite recover. Cycles of drug treatment and parasite recovery were repeated until phenotypic resistance appeared. RESULTS: After undergoing 3-4 cycles, phenotypic resistance was not yet found in mice treated with sulfadoxine. Nevertheless, the molecular biology of dhps gene (the target of sulfadoxine) was analyzed at the end of the RIcT cycle. There was no mutations found in the gene target. Interestingly, the appearance of gametocytes at the end of every cycle of drug treatment and parasite recovery was observed. These gametocytes later on would no longer extend their life in the RBC stage, unless mosquitoes bite the infected host. This phenomenon is similar to the case in human malaria infections treated with sulfadoxine-pyrimethamine (SP). CONCLUSIONS: In this study, the antimalarial drug sulfadoxine induced gametocytogenesis in P. berghei, which could raise the risk factor for malaria transmission.

Molecular insights into artemisinin resistance in Plasmodium falciparum: An updated review.

Malaria still poses a major burden on human health around the world, especially in endemic areas. Plasmodium resistance to several antimalarial drugs has been one of the major hindrances in control of malaria. Thus, the World Health Organization recommended artemisinin-based combination therapy (ACT) as a front-line treatment for malaria. The emergence of parasites resistant to artemisinin, along with resistant to ACT partner drugs, has led to ACT treatment failure. The artemisinin resistance is mostly related to the mutations in the propeller domain of the kelch13 (k13) gene that encodes protein Kelch13 (K13). The K13 protein has an important role in parasite reaction to oxidative stress. The most widely spread mutation in K13, with the highest degree of resistance, is a C580Y mutation. Other mutations, which are already identified as markers of artemisinin resistance, are R539T, I543T, and Y493H. The objective of this review is to provide current molecular insights into artemisinin resistance in Plasmodium falciparum. The trending use of artemisinin beyond its antimalarial effect is described. Immediate challenges and future research directions are discussed. Better understanding of the molecular mechanisms underlying artemisinin resistance will accelerate implementation of scientific findings to solve problems with malarial infection.