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Antimicrobial Agents and Chemotherapy, June 2005, p. 2294-2301, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2294-2301.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Preclinical Testing of the Nitroimidazopyran PA-824 for Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models

Anne J. Lenaerts,1* Veronica Gruppo,1 Karen S. Marietta,1 Christine M. Johnson,1 Diane K. Driscoll,1 Nicholas M. Tompkins,1 Jerry D. Rose,2 Robert C. Reynolds,2 and Ian M. Orme1

Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523,1 Drug Discovery Division, Southern Research Institute, Birmingham, Alabama 35225-53052

Received 19 November 2004/ Returned for modification 12 January 2005/ Accepted 31 January 2005

This study extends earlier reports regarding the in vitro and in vivo efficacies of the nitroimidazopyran PA-824 against Mycobacterium tuberculosis. PA-824 was tested in vitro against a broad panel of multidrug-resistant clinical isolates and was found to be highly active against all isolates (MIC < 1 µg/ml). The activity of PA-824 against M. tuberculosis was also assessed grown under conditions of oxygen depletion. PA-824 showed significant activity at 2, 10, and 50 µg/ml, similar to that of metronidazole, in a dose-dependent manner. In a short-course mouse infection model, the efficacy of PA-824 at 50, 100, and 300 mg/kg of body weight formulated in methylcellulose or cyclodextrin/lecithin after nine oral treatments was compared with those of isoniazid, rifampin, and moxifloxacin. PA-824 at 100 mg/kg in cyclodextrin/lecithin was as active as moxifloxacin at 100 mg/kg and isoniazid at 25 mg/kg and was slightly more active than rifampin at 20 mg/kg. Long-term treatment with PA-824 at 100 mg/kg in cyclodextrin/lecithin reduced the bacterial load below 500 CFU in the lungs and spleen. No significant differences in activity between PA-824 and the other single drug treatments tested (isoniazid at 25 mg/kg, rifampin at 10 mg/kg, gatifloxacin at 100 mg/kg, and moxifloxacin at 100 mg/kg) could be observed. In summary, its good activity in in vivo models, as well as its activity against multidrug-resistant M. tuberculosis and against M. tuberculosis isolates in a potentially latent state, makes PA-824 an attractive drug candidate for the therapy of tuberculosis. These data indicate that there is significant potential for effective oral delivery of PA-824 for the treatment of tuberculosis.

* Corresponding author. Mailing address: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523. Phone: (970) 491-3079. Fax: (970) 491-5125. E-mail: lenaerts{at}colostate.edu.

Antimicrobial Agents and Chemotherapy, June 2005, p. 2294-2301, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2294-2301.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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