Drugs Designed To Inhibit Human p38 Mitogen-Activated Protein Kinase Activation TreatToxoplasma gondiiandEncephalitozoon cuniculiInfection

We recently showed that the pyridinylimidazoles SB203580 and SB202190, drugs designed to block human p38 mitogen-activated protein kinase (MAPK) activation, also inhibited replication of the medically important intracellular parasiteToxoplasma gondii in cultured human fibroblasts through a direct effect on the parasite. We now show that additional pyridinylimidazole and imidazopyrimidine p38 MAPK inhibitors inhibit intracellularT. gondii replication in vitro and protect mice against fatalT. gondii infection. Mice surviving infection following treatment with p38 MAPK inhibitors were resistant to subsequentT. gondii challenge, demonstrating induction of protective immunity. Thus, drugs originally developed to block human p38 MAPK activation are useful for treatingT. gondii infection without inducing significant immunosuppression. MAPK inhibitors combined with either of the approved anti-Toxoplasma drugs sulfadiazine and pyrimethamine resulted in improved survival among mice challenged with a fatalT. gondii inoculum. A MAPK inhibitor also treated mice infected with theMicrosporidium parasiteEncephalitozoon cuniculi , suggesting that MAPK inhibitors represent a novel class of agents that may have a broad spectrum of antiparasitic activity. Preliminary studies implicate aT. gondii MAPK homologue as the target of drug action, suggesting possibilities for more-selective agents.