Amiodarone has intrinsic anti-Trypanosoma cruzi activity and acts synergistically with posaconazole

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.Fil: Benaim, Gustavo. Universidad Central de Venezuela, Facultad de Ciencias; Venezuela. Instituto Internacional de Estudios Avanzados; VenezuelaFil: Sanders, John M.. University of Illinois at Urbana; Estados UnidosFil: Garcia Marchán, Yael. Universidad Central de Venezuela, Facultad de Ciencias; VenezuelaFil: Colina, Claudia. Instituto Venezolano de Investigaciones Científicas; VenezuelaFil: Lira, Renee. Instituto Venezolano de Investigaciones Científicas; VenezuelaFil: Caldera, Aura R.. Instituto Venezolano de Investigaciones Científicas; VenezuelaFil: Payares, Gilberto. Universidad Central de Venezuela. Facultad de Ciencias; VenezuelaFil: Sanoja, Cristina. Universidad Central de Venezuela. Facultad de Ciencias; VenezuelaFil: Burgos, Juan Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Leon-Rossell, Annette. University of Illinois. Urbana - Champaign; Estados UnidosFil: Concepcion, Juan Luis. Universidad de los Andes; VenezuelaFil: Schijman, Alejandro Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Levin, Mariano Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Institut Cochin; FranciaFil: Oldfield, Eric. University of Illinois. Urbana - Champaign; Estados UnidosFil: Urbina, Julio A.. Instituto Venezolano de Investigaciones Científicas; Venezuel