Artemisinin and malaria: Current understandings of drug activation, action, and resistance

Abstract

Malaria is a disease that can be cured with antimalarial drugs if treated early and appropriately. However, parasites resistant to a new drug generally emerge within a few years after large-scale applications. Artemisinin (ART or Qinghaosu) combination therapies (ACTs) have become the major treatments for malaria after the emergence of parasites resistant to almost all classes of antimalarial drugs. Parasites with delayed parasite clearance (DPC) after ART or ACT therapies have also been reported in Southeast Asia, raising concerns of total failure of ART and its derivatives. Many classes of antimalarial drugs have been introduced to successfully treat malaria infections, including chloroquine, piperaquine, primaquine, mefloquine (MQ), pyrimethamine, sulfadoxine, ART and derivatives, etc. Regrettably, many of these drugs have been abandoned by many countries in malaria endemic regions due to the emergence of drug resistant parasites. According to World Health Organization, parasite responses to a drug can be classified into four categories (S, RI, RII, and RIII): Sensitivity (S) to a drug is defined as clearance of asexual parasitemia within seven days of the first day of treatment without recrudescence; Resistance RI is defined as clearance of asexual parasitemia as in sensitive parasites, followed by recrudescence; RII resistance is indicated by marked reduction of asexual parasitemia, but no clearance; and RIII resistance shows no marked reduction of asexual parasitemia. Currently, RII and RIII resistance to chloroquine, pyrimethamine, and other drugs have been widely reported; but residence to ART remains largely at R1 level. ART resistance was initially defined as parasites with half parasite clearance time (PC1/2)>5 h under a standard ART treatment regimen (three-day artesunate treatment at 2–4 mg kg - 1 d - 1). A second measurement is in vitro ring survival assay (RSA) that was developed based on the observation that the ring stages of some parasite strains could survive a short period of ART treatment. Another indicator of increasing ART tolerance is the elevated rate of recrudescence after ART or ACT treatments. The generation of highly reactive radicals via endoperoxide cleavage is critical for ART activation. Both free ferrous iron and heme have been proposed to be the predominant iron sources for ART activation. The heme required for ART activation can be derived from the parasite’s heme biosynthesis pathway at the early ring stage and/or from hemoglobin digestion at later stages. A large number of parasite molecules have been found to bind or interact with ART, most notably the Plasmodium falciparum ATPase 6 (PfATP6 or SERCA), phosphatidylinositol-3-kinase (PfPI3K), chloroquine resistance transporter (PfCRT), and multiple drug resistance 1 (PfMDR1). Recently, a gene encoding a parasite Kelch protein (“K13”) with a six-blade propeller domain was identified as a potential molecular marker of ART resistance in vivo (DPC>5 h) and in vitro (RSA). Various antimalarial drugs such as meflouine and piperaquine have been used as partner drugs in ACTs. However, parasites resistant to these partner drugs have also been reported, which may explain the reported slow parasite clearance after ACT treatment. The success of ACTs in treating malaria infections has generated optimism and proposals for malaria eradication by mass drug administration (MDA), and successes have been achieved from several studies. However, the impact of MDA on malaria transmission in the long term, especially in low- and moderate-transmission settings, and the potential consequences of developing drug resistance, requires careful evaluation. There are a large number of studies and publications on these related subjects, and it is impossible to include or cite all the publications in this review. Additionally, some of the issues discussed here are still being debated, requiring further investigation.