Development of Trypanosoma cruzi in vitro assays to identify compounds suitable for progression in Chagas' disease drug discovery.

PLoS Neglected Tropical Diseases
Lorna MacLeanManu De Rycker

Abstract

Chagas' disease is responsible for significant mortality and morbidity in Latin America. Current treatments display variable efficacy and have adverse side effects, hence more effective, better tolerated drugs are needed. However, recent efforts have proved unsuccessful with failure of the ergosterol biosynthesis inhibitor posaconazole in phase II clinical trials despite promising in vitro and in vivo studies. The lack of translation between laboratory experiments and clinical outcome is a major issue for further drug discovery efforts. Our goal was to identify cell-based assays that could differentiate current nitro-aromatic drugs nifurtimox and benznidazole from posaconazole. Using a panel of T. cruzi strains including the six major lineages (TcI-VI), we found that strain PAH179 (TcV) was markedly less susceptible to posaconazole in vitro. Determination of parasite doubling and cycling times as well as EdU labelling experiments all indicate that this lack of sensitivity is due to the slow doubling and cycling time of strain PAH179. This is in accordance with ergosterol biosynthesis inhibition by posaconazole leading to critically low ergosterol levels only after multiple rounds of division, and is further supported by the lac...Continue Reading

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Methods Mentioned

BETA
bioluminescence imaging
transgenic
PCR
FCS
light microscopy
genotyping

Software Mentioned

Biotek
Chromas
Operetta
IDBS Activitybase
Clustal Omega

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