Assessing anti-T. cruzi candidates in vitro for sterile cidality

by Cal M, Ioset JR, Fügi M, Mäsera P, Kaiser M. International Journal for Parasitology: Drugs and Drug Resistance 2016, doi:10.1016/j.ijpddr.2016.08.003.

Summary: It seems to be important for new drug candidates for Chagas disease to totally clear the T. cruzi infection (sterile cure), thus ensuring long-term beneficial effects for patients in the chronic indeterminate stage by avoiding relapse. The authors have adapted an in vitro system to predict the ability of a compound to deliver sterile cure. It relies on mouse peritoneal macrophages as host cells for Trypanosoma cruzi amastigotes. The macrophages do not proliferate, allowing for long-term testing and wash-out experiments. Giemsa staining followed by microscopy provides a highly sensitive and specific tool to quantify the numbers of infected host cells. Using this system the authors demonstrate that posaconazole and other CYP51 inhibitors are unable to achieve complete clearance of an established T. cruzi infection in vitro, in spite of the fact that these compounds are active at significantly lower concentrations than the reference drugs benznidazole and nifurtimox. These residual T. cruzi amastigotes were shown to be viable and infective, as demonstrated by wash-out experiments. The authors advocate characterizing any new anti-T. cruzi early stage candidates for sterile cidality early in the discovery cascade, as a surrogate for delivery of sterile cure in vivo.

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