Discussion

Chagas disease is caused by the insect-transmitted protozoan Trypanosoma cruzi and is the most important parasitic infection in Latin America, affecting 5-8 million people. The disease is characterised by an acute phase, which is partially resolved by the immune system, but then develops as a chronic life-long infection. The nitroheterocyclic compounds benznidazole (BZ) and nifurtimox (NF) are the front-line drugs. Unfortunately, they display a range of side-effects, that impact on patient compliance. Furthermore, both require bioactivation by the same parasite nitroreductase, a source of cross-resistance. There is consensus that BZ and NF are more effective against the acute stage. However, confirmative studies have been restricted by difficulties in demonstrating sterile cure. Here, we describe a systematic study of nitroheterocyclic drug efficacy using highly sensitive bioluminescence imaging of murine infections. We find both drugs are more effective at curing chronic infections, judged by treatment duration and therapeutic dose. This was not associated with factors that influence plasma drug concentrations in the two disease stages. We also observed that fexinidazole and fexinidazole sulfone are more effective than BZ and NF as curative treatments, particularly for acute stage infection, and that this is associated with higher and more prolonged exposure of the sulfone derivative.