Abstract
Atovaquone-proguanil (Malarone®) is used for malaria prophylaxis and treatment. While the cytochrome bc1-inhibitor atovaquone has potent activity, proguanil’s action is attributed to its cyclization-metabolite, cycloguanil. Evidence suggests that proguanil has limited intrinsic activity, associated with mitochondrial-function. Here we demonstrate that proguanil, and cyclization-blocked analogue tBuPG, have potent, but slow-acting, in vitro anti-plasmodial activity. Activity is folate-metabolism and isoprenoid biosynthesis-independent. In yeast dihydroorotate dehydrogenase-expressing parasites, proguanil and tBuPG slow-action remains, while bc1-inhibitor activity switches from comparatively fast to slow-acting. Like proguanil, tBuPG has activity against P. berghei liver-stage parasites. Both analogues act synergistically with bc1-inhibitors against blood-stages in vitro, however cycloguanil antagonizes activity. Together, these data suggest that proguanil is a potent slow-acting anti-plasmodial agent, that bc1 is essential to parasite survival independent of dihydroorotate dehydrogenase-activity, that Malarone® is a triple-drug combination that includes antagonistic partners and that a cyclization-blocked proguanil may be a superior combination partner for bc1-inhibitors in vivo.
Highlights
Atovaquone-proguanil (Malarone®) is used for malaria prophylaxis and treatment
The potent fastacting activity of proguanil is attributed to the dihydrofolate reductase inhibitor cycloguanil (the product of liver cytochrome P450 (CYP2C19) metabolism2) and resistance has been shown to be mediated by dihydrofolate reductase mutations[3]
The intrinsic in vitro activity of proguanil against asexual blood stage parasites is not completely understood, studies have shown that parasites with impaired mitochondrial electron transport chain function are hypersensitive to proguanil[5,14,15,29]
Summary
Atovaquone-proguanil (Malarone®) is used for malaria prophylaxis and treatment. While the cytochrome bc1-inhibitor atovaquone has potent activity, proguanil’s action is attributed to its cyclization-metabolite, cycloguanil. To overcome clinical parasite resistance, and following the finding that proguanil can potentiate (increase>1000-fold) the activity of atovaquone (a cytochrome bc[1] or mitochondrial electron transport chain complex III inhibitor4,5) the atovaquone-proguanil combination, Malarone®, was developed. In a study on the island of Malakula, Vanuatu, high antimalarial efficacy of proguanil monotherapy was observed in patients with CYP2C19related poor proguanil metabolizer genotypes[21] Together, these observations suggest that, in addition to factors such as the presence or absence of pre-existing resistance of infecting parasites to atovaquone and/or cycloguanil[1,27,28], variations in how well individuals metabolise proguanil to cycloguanil[21,26] may have an impact on the in vivo activity of Malarone®. The intrinsic (i.e., in absence of metabolism) in vitro activity of proguanil against asexual blood stage parasites is not completely understood, studies have shown that parasites with impaired mitochondrial electron transport chain function are hypersensitive to proguanil[5,14,15,29].
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