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 DATABASES 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...

Clinical studies and mathematical models predict that, to achieve malaria elimination, combination therapies will need to incorporate drugs that block the transmission of Plasmodium falciparum sexual stage parasites to mosquito vectors. Efforts to measure the activity of existing antimalarials on intraerythrocytic sexual stage gametocytes and identify transmission-blocking agents have, until now, been hindered by a lack of quantitative assays. Here, we report an experimental system using P. falciparum lines that stably express gametocyte-specific GFP-luciferase reporters, which enable the assessment of dose-and time-dependent drug action on gametocyte maturation and transmission. These studies reveal activity of the first-line antimalarial dihydroartemisinin and the partner drugs lumefantrine and pyronaridine against early gametocyte stages, along with moderate inhibition of mature gametocyte transmission to Anopheles mosquitoes. The other partner agents monodesethyl-amodiaquine and piperaquine showed activity only against immature gametocytes. Our data also identify methylene blue as a potent inhibitor of gametocyte development across all stages. This thiazine dye almost fully abolishes P. falciparum transmission to mosquitoes at concentrations readily achievable in humans, highlighting the potential of this chemical class to reduce the spread of malaria.artemisinin-based combination therapies | transfection

Edited by Sergio Papa, Gianfranco Gilardi and Wilhelm JustKeywords: Drug resistance Antimalarial drug pfcrt pfmdr1 Plasmodium falciparum Plasmodium vivax a b s t r a c tResistance to antimalarial drugs has often threatened malaria elimination efforts and historically has led to the short-term resurgence of malaria incidences and deaths. With concentrated malaria eradication efforts currently underway, monitoring drug resistance in clinical settings complemented by in vitro drug susceptibility assays and analysis of resistance markers, becomes critical to the implementation of an effective antimalarial drug policy. Understanding of the factors, which lead to the development and spread of drug resistance, is necessary to design optimal prevention and treatment strategies. This review attempts to summarize the unique factors presented by malarial parasites that lead to the emergence and spread of drug resistance, and gives an overview of known resistance mechanisms to currently used antimalarial drugs.

Malaria parasites are transmitted by mosquitoes, and blocking parasite transmission is critical in reducing or eliminating malaria in endemic regions. Here, we report the pharmacological characterization of a new class of malaria transmission-blocking compounds that acts via the inhibition of Plasmodia CDPK4 enzyme. We demonstrate that these compounds achieved selectivity over mammalian kinases by capitalizing on a small serine gatekeeper residue in the active site of the Plasmodium CDPK4 enzyme. To directly confirm the mechanism of action of these compounds, we generated P. falciparum parasites that express a drug-resistant methionine gatekeeper (S147 M) CDPK4 mutant. Mutant parasites showed a shift in exflagellation EC50 relative to the wild-type strains in the presence of compound 1294, providing chemical-genetic evidence that CDPK4 is the target of the compound. Pharmacokinetic analyses suggest that coformulation of this transmission-blocking agent with asexual stage antimalarials such as artemisinin combination therapy (ACT) is a promising option for drug delivery that may reduce transmission of malaria including drug-resistant strains. Ongoing studies include refining the compounds to improve efficacy and toxicological properties for efficient blocking of malaria transmission.