Screening the MMV Pathogen Box againstToxoplasma gondiiTachyzoites and Bradyzoites Identifies Dually Cidalbc1-complex Inhibitors

Abstract

AbstractThe apicomplexan parasiteToxoplasma gondiiinfects 25-30% of the global human population and can cause life-threatening diseases in immunocompromised patients. The chronic infectious form of the parasite, bradyzoites, persist within cysts in brain and muscle tissues and are responsible for its transmission and remission. Currently available treatment options are very limited and include antimicrobials currently in development novel developmental treatments. They are only effective against the fast replicating tachyzoites but fail to eradicate the chronic stages ofT. gondii. The cause of these treatment failures remains unclear. We utilized the recently developed human myotube-based culture model to screen compounds from the MMV Pathogen Box against pan-drug tolerantin vitrobradyzoites. We identified various hit compounds that show simultaneous activity against tachyzoites and bradyzoites. Stable isotope-resolved metabolic profiling identified the mitochondrial bc1-complex as a target of bradyzocidal compounds. Comparing the impact of bradyzocidal with non-bradyzocidal coenzyme Q analogs on parasite ATP levels suggests active and essential mitochondrial ATP production in mature bradyzoites.