Toxoplasma gondii, an obligate intracellular parasite that can cause life-threatening
acute disease, differentiates into a quiescent
cyst stage to establish lifelong
chronic infections in animal hosts, including humans. This tissue
cyst reservoir, which can reactivate into an acute
infection, is currently refractory to clinically available
therapeutics. Recently, we and others have discovered drugs capable of significantly reducing the brain
cyst burden in latently infected mice, but not to undetectable levels. In this study, we examined the use of novel combination
therapies possessing multiple mechanisms of action in mouse models of latent
toxoplasmosis. Our
drug regimens included combinations of
pyrimethamine,
clindamycin,
guanabenz, and endochin-like
quinolones (ELQs) and were administered to two different mouse strains in an attempt to eradicate brain tissue
cysts. We observed mouse strain-dependent effects with these
drug treatments:
pyrimethamine-
guanabenz showed synergistic efficacy in C57BL/6 mice yet did not improve upon
guanabenz monotherapy in BALB/c mice. Contrary to promising in vitro results demonstrating toxicity to bradyzoites, we observed an antagonistic effect between
guanabenz and ELQ-334 in vivo While we were unable to completely eliminate the brain
cyst burden, we found that a combination treatment with ELQ-334 and
pyrimethamine impressively reduced the brain
cyst burden by 95% in C57BL/6 mice, which approached the limit of detection. These analyses highlight the importance of evaluating anti-infective drugs in multiple mouse strains and will help inform further preclinical studies of cocktail
therapies designed to treat chronic
toxoplasmosis.