Plasmodium falciparum resistance to chloroquine and sulphadoxine-pyrimethamine has led to the recent adoption of artemisinin-based combination therapies (ACTs) as the first line of treatment against malaria. ACTs comprise semisynthetic artemisinin derivatives paired with distinct chemical classes of longer acting drugs. These artemisinins are exceptionally potent against the pathogenic asexual blood stages of Plasmodium parasites and also act on the transmissible sexual stages. These combinations increase the rates of clinical and parasitological cures and decrease the selection pressure for the emergence of antimalarial resistance. This Review article discusses our current knowledge about the mode of action of ACTs, their pharmacological properties and the proposed mechanisms of drug resistance.Six decades ago, hopes of malaria eradication were raised by the discovery and implementation of chloroquine (CQ). The use of this highly effective, fast-acting and inexpensive 4-aminoquinoline, along with the potent insecticide dichlorodiphenyltrichloroethane (DDT), quickly proved successful in substantially reducing the incidence and severity of malaria worldwide. Initial successes were achieved primarily in regions with temperate climates and seasonal malaria transmission. However, in many parts of the world eradication efforts were effectively thwarted by multiple issues, including insecticide resistance in Anopheles mosquito vectors, high rates of Plasmodium parasite transmission, logistical hurdles to implementing
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NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript control strategies, wars and population displacements, and a lack of sustained funding. Subsequently, resistance to CQ and the cost-effective replacement drug sulphadoxinepyrimethamine (SP) emerged in the most lethal human malarial pathogen, Plasmodium falciparum 1,2 . In some areas, the switch to either mefloquine (MFQ) or quinine resulted in the appearance of multidrug-resistant parasites, particularly in Southeast Asia 3 . The global consequence was a resurgence of malaria morbidity and mortality. With nearly 40% of the global population at risk, 300-660 million episodes of clinical P. falciparum malaria occur annually and there are an estimated one million deaths 4 . Most of these occur in sub-Saharan Africa (FIG. 1a), where rates of transmission can reach 1,500 mosquito-delivered parasite inoculations per individual per year 5 .Now there is hope that the tide may turn again with the implementation of artemisinin-based combination therapies (ACTs). Their success in treating CQ-and SP-resistant malaria has prompted the WHO to recommend ACTs as the preferred first-line antimalarials against P. falciparum malaria and has elicited substantial funding and logistical support from, among others, The Global Fund to Fight AIDS, Tuberculosis, and Malaria, The World Bank, Roll Back Malaria, the President's Malaria Initiative, the Medicines for Malaria Venture, and the Bill and Melinda Gates Foundation. ACTs have now been...