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Antimicrobial Agents and Chemotherapy, February 2002, p. 300-307, Vol. 46, No. 2
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.2.300-307.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Evaluation of a Cyclic GMP-Dependent Protein Kinase Inhibitor in Treatment of Murine Toxoplasmosis: Gamma Interferon Is Required for Efficacy

Bakela Nare,* John J. Allocco, Paul A. Liberator, and Robert G. K. Donald

Department of Human and Animal Infectious Disease Research, Merck Research Laboratories, Merck and Co., Inc., Rahway, New Jersey 07076

Received 28 August 2001/ Returned for modification 19 September 2001/ Accepted 24 October 2001

The trisubstituted pyrrole 4-[2-(4-fluorophenyl)-5-(1-methylpiperidine-4-yl)-1H-pyrrol-3-yl]pyridine (compound 1) is a potent inhibitor of cyclic GMP-dependent protein kinases from Apicomplexan protozoa and displays cytostatic activity against Toxoplasma gondii in vitro. Compound 1 has now been evaluated against T. gondii infections in the mouse and appeared to protect the animals when given intraperitoneally at 50 mg/kg twice daily for 10 days. However, samples from brain, spleen, and lung taken from infected treated mice revealed the presence of parasites after cessation of administration of compound 1, indicating that a transient asymptomatic parasite recrudescence occurs in all survivors. The ability of mice to control Toxoplasma infection after compound 1 treatment has been terminated suggested that the mouse immune system plays a synergistic role with chemotherapy in controlling the infection. To explore this possibility, gamma interferon (IFN-{gamma})-knockout mice were infected with parasites and treated with compound 1, and survival was compared to that of normal mice. IFN-{gamma}-knockout mice were protected against T. gondii throughout the treatment phase but died during the posttreatment phase in which peak recrudescence was observed in treated immunocompetent mice. These data suggest that an IFN-{gamma}-dependent immune response was essential for controlling and resolving parasite recrudescence in mice treated with compound 1. In addition, when compound 1-cured immunocompetent mice were rechallenged with a lethal dose of T. gondii, all survived (n = 32). It appears that the cytostatic nature of compound 1 provides an "immunization" phase during chemotherapy which allows the mice to survive the recrudescence and any subsequent challenge with a lethal dose of T. gondii.

* Corresponding author. Mailing address: Department of Human and Animal Infectious Disease Research, Merck Research Laboratories, Merck and Co., Inc., P.O. Box 2000, Rahway, NJ 07076. Phone: (732) 594-4332. Fax: (732) 594-6708. E-mail: bakela_nare{at}merck.com.

Antimicrobial Agents and Chemotherapy, February 2002, p. 300-307, Vol. 46, No. 2
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.2.300-307.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Gubbels, M.-J., Li, C., Striepen, B. (2003). High-Throughput Growth Assay for Toxoplasma gondii Using Yellow Fluorescent Protein. Antimicrob. Agents Chemother. 47: 309-316 [Abstract] [Full Text]  
  • Donald, R. G. K., Allocco, J., Singh, S. B., Nare, B., Salowe, S. P., Wiltsie, J., Liberator, P. A. (2002). Toxoplasma gondii Cyclic GMP-Dependent Kinase: Chemotherapeutic Targeting of an Essential Parasite Protein Kinase. Eukaryot Cell 1: 317-328 [Abstract] [Full Text]  
  • Gurnett, A. M., Liberator, P. A., Dulski, P. M., Salowe, S. P., Donald, R. G. K., Anderson, J. W., Wiltsie, J., Diaz, C. A., Harris, G., Chang, B., Darkin-Rattray, S. J., Nare, B., Crumley, T., Blum, P. S., Misura, A. S., Tamas, T., Sardana, M. K., Yuan, J., Biftu, T., Schmatz, D. M. (2002). Purification and Molecular Characterization of cGMP-dependent Protein Kinase from Apicomplexan Parasites. A NOVEL CHEMOTHERAPEUTIC TARGET. J. Biol. Chem. 277: 15913-15922 [Abstract] [Full Text]  


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