Amiodarone Has Intrinsic Anti-<i>Trypanosoma </i><i>c</i><i>ruzi</i> Activity and Acts Synergistically with Posaconazole

TLDR

Chagas disease lacks effective chronic therapy; the parasite T. cruzi depends on ergosterol, making ergosterol inhibitors like posaconazole potent, and amiodarone, an antiarrhythmic, also shows antifungal activity.

Abstract

There is no effective treatment for the prevalent chronic form of Chagas' disease in Latin America. Its causative agent, the protozoan parasite Trypanosoma cruzi, has an essential requirement for ergosterol, and ergosterol biosynthesis inhibitors, such as the antifungal drug posaconazole, have potent trypanocidal activity. The antiarrhythmic compound amiodarone, frequently prescribed for the symptomatic treatment of Chagas' disease patients, has also recently been shown to have antifungal activity. We now show here for the first time that amiodarone has direct activity against T. cruzi, both in vitro and in vivo, and that it acts synergistically with posaconazole. We found that amiodarone, in addition to disrupting the parasites' Ca2+ homeostasis, also blocks ergosterol biosynthesis, and that posaconazole also affects Ca2+ homeostasis. These results provide logical explanations for the synergistic activity of amiodarone with azoles against T. cruzi and open up the possibility of novel, combination therapy approaches to the treatment of Chagas' disease using currently approved drugs.