The potential of the antifungal nystatin to be repurposed to fight the protozoan Trypanosoma cruzi

Abstract

Chagas disease, caused by the parasite Trypanosoma cruzi, affects 6 million peopleworldwide. Although the drugs benznidazole (BZN) and nifurtimox are availableto treat Chagas, they are not effective in the chronic phase when most patientsare diagnosed. Moreover, long-term regimen and severe side effects often leadto poor adherence and treatment abandonment. These problems highlight theurgent need to develop new therapies to treat this neglected disease. Given thatthe antifungal drug nystatin (NYS) affects arginine uptake in yeasts, and fluctuationson arginine availability through transport processes in T. cruzi can negatively affectits viability, in this work we evaluated the potential of NYS for drug repurposingagainst T. cruzi. NYS inhibited arginine uptake and presented trypanocidal effect inboth epimastigotes (IC50 0.17 μM) and trypomastigotes (IC50 4.90 μM). In addition,treatment of infected cells with NYS decreased the release of trypomastigotes withbetter efficacy than BZN (IC50s 4.83 μM and 8.60 μM, respectively) suggesting thatNYS affects the progression of the intracellular life cycle. Furthermore, we observeda synergistic effect both in isolated trypomastigotes and infected cells when NYSwas combined with BZN, which could enhance efficacy while improving treatmentsafety and adherence. As in yeasts, the mechanism of action of NYS in T. cruziinvolved the plasma membrane disruption, and membrane transport processes, likeamino acids and thymidine uptake, were affected prior to the disruption probablydue to NYS interaction with the membrane. Drug repurposing is a recommendedstrategy by the World Health Organization to develop new therapeutic alternativesfor neglected diseases. Our results indicate that NYS presents great potential tobe repurposed as a trypanocidal drug to fight T. cruzi.