Drugs designed to inhibit human p38 mitogen-activated protein kinase activation treat Toxoplasma gondii and Encephalitozoon cuniculi infection

Shuang Wei, Benjamin J. Daniel, Michael J. Brumlik, Matthew E. Burow, Weiping Zou, Imtiaz A. Khan, Scott Wadsworth, John Siekierka, Tyler J. Curiel

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4324-4328
Number of pages5
JournalAntimicrobial Agents and Chemotherapy
Volume51
Issue number12
DOIs
StatePublished - 1 Dec 2007

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Encephalitozoon cuniculi
Toxoplasma
p38 Mitogen-Activated Protein Kinases
Protein Kinase Inhibitors
Mitogen-Activated Protein Kinases
Infection
Pharmaceutical Preparations
Parasites
Toxoplasmosis
Unclassified Microsporidia
Sulfadiazine
Antiparasitic Agents
Pyrimethamine
Immunosuppression
Immunity
Fibroblasts
Survival

Cite this

Wei, Shuang ; Daniel, Benjamin J. ; Brumlik, Michael J. ; Burow, Matthew E. ; Zou, Weiping ; Khan, Imtiaz A. ; Wadsworth, Scott ; Siekierka, John ; Curiel, Tyler J. / Drugs designed to inhibit human p38 mitogen-activated protein kinase activation treat Toxoplasma gondii and Encephalitozoon cuniculi infection. In: Antimicrobial Agents and Chemotherapy. 2007 ; Vol. 51, No. 12. pp. 4324-4328.
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Drugs designed to inhibit human p38 mitogen-activated protein kinase activation treat Toxoplasma gondii and Encephalitozoon cuniculi infection. / Wei, Shuang; Daniel, Benjamin J.; Brumlik, Michael J.; Burow, Matthew E.; Zou, Weiping; Khan, Imtiaz A.; Wadsworth, Scott; Siekierka, John; Curiel, Tyler J.

In: Antimicrobial Agents and Chemotherapy, Vol. 51, No. 12, 01.12.2007, p. 4324-4328.

Research output: Contribution to journalArticle

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