BACKGROUND: New safe and effective treatments for Chagas disease (CD) are 
urgently needed. Current chemotherapy options for CD have significant 
limitations, including failure to uniformly achieve parasitological cure or 
prevent the chronic phase of CD, and safety and tolerability concerns. 
Fexinidazole, a 2-subsituted 5-nitroimidazole drug candidate rediscovered 
following extensive compound mining by the Drugs for Neglected Diseases 
initiative and currently in Phase I clinical study for the treatment of human 
African trypanosomiasis, was evaluated in experimental models of acute and 
chronic CD caused by different strains of Trypanosoma cruzi.
METHODS AND FINDINGS: We investigated the in vivo activity of fexinidazole 
against T. cruzi, using mice as hosts. The T. cruzi strains used in the study 
were previously characterized in murine models as susceptible (CL strain), 
partially resistant (Y strain), and resistant (Colombian and VL-10 strains) to 
the drugs currently in clinical use, benznidazole and nifurtimox. Our results 
demonstrated that fexinidazole was effective in suppressing parasitemia and 
preventing death in infected animals for all strains tested. In addition, 
assessment of definitive parasite clearance (cure) through parasitological, PCR, 
and serological methods showed cure rates of 80.0% against CL and Y strains, 
88.9% against VL-10 strain, and 77.8% against Colombian strain among animals 
treated during acute phase, and 70% (VL-10 strain) in those treated in chronic 
phase. Benznidazole had a similar effect against susceptible and partially 
resistant T. cruzi strains. Fexinidazole treatment was also shown to reduce 
myocarditis in all animals infected with VL-10 or Colombian resistant T. cruzi 
strains, although parasite eradication was not achieved in all treated animals 
at the tested doses.
CONCLUSIONS: Fexinidazole is an effective oral treatment of acute and chronic 
experimental CD caused by benznidazole-susceptible, partially resistant, and 
resistant T. cruzi. These findings illustrate the potential of fexinidazole as a 
drug candidate for the treatment of human CD.