High-Throughput Repurposing Screen Reveals Compounds with Activity against Toxoplasma gondii Bradyzoites.

Abstract

Toxoplasma gondii causes widespread chronic infections that are not cured by current treatments due to the inability to affect semidormant bradyzoite stages within tissue cysts. To identify compounds to eliminate chronic infection, we developed an HTS using a recently characterized strain of T. gondii that undergoes efficient conversion to bradyzoites in vitro. Stage-specific expression of luciferase was used to selectively monitor the growth inhibition of bradyzoites by the Library of Pharmacological Active Compounds, consisting of 1280 drug-like compounds. We identified 44 compounds with >50% inhibitory effects against bradyzoites, including new highly potent compounds, several of which have precedent for antimicrobial activity. Subsequent characterization of the compound sanguinarine sulfate revealed potent and rapid killing against in vitro-produced bradyzoites and bradyzoites harvested from chronically infected mice, including potent activity against intact cysts. These findings provide a platform for expanded screening and identify promising compounds for further preclinical development against T. gondii bradyzoites that are responsible for chronic infection.