New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections
Résumé
Toxoplasma gondii, the most common parasitic infection of human brain and eye, persists across lifetimes, can progressively damage sight, and is currently incurable. New, curative medicines are needed urgently. Herein, we develop novel models to facilitate drug development: EGS strain T. gondii forms cysts in vitro that induce oocysts in cats, the gold standard criterion for cysts. These cysts highly express cytochrome b. Using these models, we envisioned, and then created, novel 4-(1H)-quinolone scaffolds that target the cytochrome bc(1) complex Q(i) site, of which, a substituted 5,6,7,8-tetrahydroquinolin-4-one inhibits active infection (IC50, 30 nM) and cysts (IC50, 4 mu M) in vitro, and in vivo (25 mg/kg), and drug resistant Plasmodium falciparum (IC50, \textless 30 nM), with clinically relevant synergy. Mutant yeast and co-crystallographic studies demonstrate binding to the bc(1) complex Q(i) site. Our results have direct impact on improving outcomes for those with toxoplasmosis, malaria, and similar to 2 billion persons chronically infected with encysted bradyzoites.