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Abstract
Toxoplasma gondii is a protozoan parasite that can infect many warm-blooded animals,including humans and can cause devastating disease in immunocompromised individuals and the
unborn fetus. The current treatments against toxoplasmosis are only effective against the acute
stages with little effect against bradyzoites found in tissue cysts. The mitochondrion of T. gondii
is a validated target and one of the major anti-toxoplasma drugs, atovaquone, inhibits the
mitochondrial electron transport chain (ETC) through inhibition of the coenzyme Q:cytochrome c
oxidoreductase. Herein we show that inhibition of the synthesis of the Ubiquinone (UQ) isoprenoid
tail by lipophilic bisphosphonates was an effective way to control the acute and chronic infections
with T. gondii. We developed a UQ rescue screen to test libraries of compounds to find inhibitors
of the UQ synthesis pathway. In addition, we tested inhibitors of the mitochondrial electron
transport chain and found several derivatives that were effective at decreasing bradyzoite viability
and one that was able to protect mice against a lethal acute infection. We also monitored the
activity of mice during the acute and chronic stages of disease using a new CageDot sensor that
measures activity continuously throughout the entire infection and in their home cage environment.
Through this we show that mice become hyperactive during chronic infection and this increase in
activity is ameliorated upon treatment with bisphosphonates. Altogether we show that inhibition
of the UQ pathway and the electron transport chain are viable targets for improved chemotherapy
of the acute and chronic stages of toxoplasmosis.