Animal models for exploring Chagas disease pathogenesis and supporting drug discovery.

Infections with the parasitic protozoan cause Chagas disease, which results in serious cardiac and/or digestive pathology in 30%-40% of individuals. However, symptomatic disease can take decades to become apparent, and there is a broad spectrum of possible outcomes. The complex and long-term nature of this infection places a major constraint on the scope for experimental studies in humans.

A panel of phenotypically and genotypically diverse bioluminescent:fluorescent Trypanosoma cruzi strains as a resource for Chagas disease research.

Chagas disease is caused by Trypanosoma cruzi, a protozoan parasite that displays considerable genetic diversity. Infections result in a range of pathological outcomes, and different strains can exhibit a wide spectrum of anti-parasitic drug tolerance. The genetic determinants of infectivity, virulence and therapeutic susceptibility remain largely unknown.

Benznidazole treatment leads to DNA damage in Trypanosoma cruzi and the persistence of rare widely dispersed non-replicative amastigotes in mice.

Benznidazole is the front-line drug used to treat infections with Trypanosoma cruzi, the causative agent of Chagas disease. However, for reasons that are unknown, treatment failures are common. When we examined parasites that survived benznidazole treatment in mice using highly sensitive in vivo and ex vivo bioluminescence imaging, we found that recrudescence is not due to persistence of parasites in a specific organ or tissue that preferentially protects them from drug activity.

Bis-6-amidino-benzothiazole Derivative that Cures Experimental Stage 1 African Trypanosomiasis with a Single Dose.

We designed and synthesized a series of symmetric bis-6-amidino-benzothiazole derivatives with aliphatic central units and evaluated their efficacy against bloodstream forms of the African trypanosome . Of these, a dicationic benzothiazole compound () exhibited sub-nanomolar in vitro potency with remarkable selectivity over mammalian cells (>26,000-fold). Unsubstituted 5-amidine groups and a cyclohexyl spacer were the crucial determinants of trypanocidal activity.

Dissecting the interstrand crosslink DNA repair system of Trypanosoma cruzi.

DNA interstrand crosslinks (ICLs) are toxic lesions that can block essential biological processes. Here we show Trypanosoma cruzi, the causative agent of Chagas disease, is susceptible to ICL-inducing compounds including mechlorethamine and novel nitroreductase-activated prodrugs that have potential in treating this infection. To resolve such lesions, cells co-opt enzymes from "classical" DNA repair pathways that alongside dedicated factors operate in replication-dependent and -independent mechanisms.