Drugs designed to inhibit human p38 mitogen-activated protein kinase activation treat Toxoplasma gondii and Encephalitozoon cuniculi infection.
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 parasite Toxoplasma gondii in cultured human fibroblasts through a direct effect on the parasite. We now show that additional pyridinylimidazole and imidazopyrimidine p38 MAPK inhibitors inhibit intracellular T. gondii replication in vitro and protect mice against fatal T. gondii infection. Mice surviving infection following treatment with p38 MAPK inhibitors were resistant to subsequent T. gondii challenge, demonstrating induction of protective immunity. Thus, drugs originally developed to block human p38 MAPK activation are useful for treating T. 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 fatal T. gondii inoculum. A MAPK inhibitor also treated mice infected with the Microsporidium parasite Encephalitozoon cuniculi, suggesting that MAPK inhibitors represent a novel class of agents that may have a broad spectrum of antiparasitic activity. Preliminary studies implicate a T. gondii MAPK homologue as the target of drug action, suggesting possibilities for more-selective agents.
Wei
Shuang
S
Department of Medicine (Hematology and Medical Oncology), Tulane University School of Medicine, 1430 Tulane Avenue SL-78, New Orleans, Louisiana 70112, USA.
Daniel
Benjamin J
BJ
Brumlik
Michael J
MJ
Burow
Matthew E
ME
Zou
Weiping
W
Khan
Imtiaz A
IA
Wadsworth
Scott
S
Siekierka
John
J
Curiel
Tyler J
TJ
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D016827:CD8 Antigens / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D009670:Encephalitozoon cuniculi / Q000187:drug effects; D016890:Encephalitozoonosis / Q000188:drug therapy* / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D011725:Pyridines / Q000494:pharmacology; D013997:Time Factors; D014122:Toxoplasma / Q000187:drug effects; D014124:Toxoplasmosis, Animal / Q000188:drug therapy* / Q000235:genetics / Q000517:prevention & control; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D000981:Antiprotozoal Agents; D016827:CD8 Antigens; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole