Plasmodium falciparum Ferredoxin-NADP+ Reductase-Catalyzed Redox Cycling of Plasmodione Generates Both Predicted Key Drug Metabolites: Implication for Antimalarial Drug Development

In addition to good stewardship, the unabated rise in herbicide resistance and dearth of truly new herbicides demands that new molecules be found. Over 30 years ago, a chloroplast-like organelle was found in the malarial parasite Plasmodium falciparum and herbicides demonstrated a close relationship existed to plants. Recently this idea was turned on its head by exploiting the boom in malaria research to search for new herbicide chemistry and it provided interesting starting points for development. The merit of such an approach is underlined by tetflupyrolimet, the first truly novel herbicide in 30 years, and whose target has been a popular subject for antimalarial drug development for 15 years. Which other antimalarial targets, drugs and drug leads might reach across the parasite-plant divide to inspire new herbicides?

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Novel inhibitors of the Plasmodium falciparum electron transport chain

Parasitology ◽

10.1017/s0031182013001571 ◽

2014 ◽

Vol 141 (1) ◽

pp. 50-65 ◽

Cited By ~ 21

Author(s):

P. A. STOCKS ◽

V. BARTON ◽

T. ANTOINE ◽

G. A. BIAGINI ◽

S. A. WARD ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Electron Transport ◽

Drug Development ◽

Antimalarial Drug ◽

Electron Transport Chain ◽

Type Ii ◽

Dihydroorotate Dehydrogenase ◽

Cytochrome Bc ◽

Transport Chain ◽

Promising Area

SUMMARYDue to an increased need for new antimalarial chemotherapies that show potency against Plasmodium falciparum, researchers are targeting new processes within the parasite in an effort to circumvent or delay the onset of drug resistance. One such promising area for antimalarial drug development has been the parasite mitochondrial electron transport chain (ETC). Efforts have been focused on targeting key processes along the parasite ETC specifically the dihydroorotate dehydrogenase (DHOD) enzyme, the cytochrome bc1 enzyme and the NADH type II oxidoreductase (PfNDH2) pathway. This review summarizes the most recent efforts in antimalarial drug development reported in the literature and describes the evolution of these compounds.

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Atovaquone Tolerance in Plasmodium falciparum Parasites Selected for High-Level Resistance to a Dihydroorotate Dehydrogenase Inhibitor

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02347-14 ◽

2014 ◽

Vol 59 (1) ◽

pp. 686-689 ◽

Cited By ~ 9

Author(s):

Jennifer L. Guler ◽

John White ◽

Margaret A. Phillips ◽

Pradipsinh K. Rathod

Keyword(s):

Plasmodium Falciparum ◽

Drug Development ◽

Cross Talk ◽

Antimalarial Drug ◽

Pyrimidine Biosynthesis ◽

Dihydroorotate Dehydrogenase ◽

Development Programs ◽

Genetic Cross ◽

High Level ◽

Level Resistance

ABSTRACTAtovaquone is a component of Malarone, a widely prescribed antimalarial combination, that targets malaria respiration. Here we show that parasites with high-level resistance to an inhibitor of dihydroorotate dehydrogenase demonstrate unexpected atovaquone tolerance. Fortunately, the tolerance is diminished with proguanil, the second partner in Malarone. It is important to understand such “genetic cross talk” between respiration and pyrimidine biosynthesis since many antimalarial drug development programs target these two seemingly independent pathways.

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