Nitroheterocyclic drugs cure experimental Trypanosoma cruzi infections more effectively in the chronic stage than in the acute stage

Abstract

The insect-transmitted protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, and infects 5–8 million people in Latin America. Chagas disease is characterised by an acute phase, which is partially resolved by the immune system, but then develops as a chronic life-long infection. There is a consensus that the front-line drugs benznidazole and nifurtimox are more effective against the acute stage in both clinical and experimental settings. However, confirmative studies have been restricted by difficulties in demonstrating sterile parasitological cure. Here, we describe a systematic study of nitroheterocyclic drug efficacy using highly sensitive bioluminescence imaging of murine infections. Unexpectedly, 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 differentially influence plasma drug concentrations in the two disease stages. We also observed that fexinidazole and fexinidazole sulfone are more effective than benznidazole and nifurtimox as curative treatments, particularly for acute stage infections, most likely as a result of the higher and more prolonged exposure of the sulfone derivative. If these findings are translatable to human patients, they will have important implications for treatment strategies.

3D mapping of host-parasite-microbiome interactions reveals metabolic determinants of tissue tropism and disease tolerance in Chagas disease

“…3 ). It is tempting to speculate a microbiota-mediated mechanism of reduced antiparasitic immune responses in the cecum, perhaps via cecal microbiota-derived short-chain fatty acid 26 , or induction of parasite dormancy at this site 27 , leading to the observed parasite recrudescence in the cecum following incomplete posaconazole or nifurtimox treatment 828 , and this awaits further experimentation. Lastly, the spatially-resolved metabolomic and microbiome methods that we illustrate here with T. cruzi can readily be applied to study other pathogens with specific tissue tropism, and we anticipate this approach to have broad applicability.…”

Chagas disease research and development: Is there light at the end of the tunnel?

“…There are some isolated cases and non-controlled studies showing that this could also be the case in adults [30], [31], [32], [33], [34], [35]. New data from a BLI animal model showed recently that chronically infected mice could be cured with only 5 days' treatment with a standard dose of benznidazole and that a reduction of the dose is possible but requires longer treatment [36]. This will be extremely promising if these experimental studies translate into clinical trials.…”

Hydroxymethylnitrofurazone treatment in indeterminate form of chronic Chagas disease: Reduced intensity of tissue parasitism and inflammation—A histopathological study

“…The current available drugs are effective in the acute phase of the disease and act against amastigotes of some strains of T. cruzi in late acute, indeterminate, and chronic phases of Chagas disease. But they do not exhibit activity against the Y strain of T. cruzi during the later phases . So, the purpose of this work was to evaluate the effect of NFOH in several tissues (heart, colon, liver, kidney, spleen, brain and skeletal muscle) during the indeterminate form of the disease, induced by the Y strain of T. cruzi in BALB/c male mice.…”

“…But they do not exhibit activity against the Y strain of T. cruzi during the later phases. [25][26][27][28][29][30][31][32][33][34][35] So, the purpose of this work was to evaluate the effect of NFOH in several tissues (heart, colon, liver, kidney, spleen, brain and skeletal muscle) during the indeterminate form of the disease, induced by the Y strain of T. cruzi in BALB/c male mice.…”