Cyclization-blocked proguanil as a strategy to improve the antimalarial activity of atovaquone.

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Journal:
Communications biology, Volume: 2
Published:
May 3, 2019
PMID:
31069275
Authors:
Tina S Skinner-Adams TS, Gillian M Fisher GM, Andrew G Riches AG, Oliver E Hutt OE, Karen E Jarvis KE, Tony Wilson T, Mark von Itzstein M, Pradeep Chopra P, Yevgeniya Antonova-Koch Y, Stephan Meister S, Elizabeth A Winzeler EA, Mary Clarke M, David A Fidock DA, Jeremy N Burrows JN, John H Ryan JH, Katherine T Andrews KT
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 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.