Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models.

Abstract

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 microg/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 microg/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.

• Authors: Anne J Lenaerts, Veronica Gruppo, Karen S Marietta, Christine M Johnson, Diane K Driscoll, Nicholas M Tompkins, Jerry D Rose, Robert C Reynolds, Ian M Orme
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 49 Issue 6 Pg. 2294-301 (Jun 2005) ISSN: 0066-4804 [Print] United States
• PMID: 15917524 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antitubercular Agents
• Nitroimidazoles
• pretomanid

Topics

• Animals
• Antitubercular Agents (administration & dosage, pharmacology, therapeutic use)
• Colony Count, Microbial
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Female
• Humans
• Lung (microbiology)
• Mice
• Mice, Inbred C57BL
• Microbial Sensitivity Tests
• Mycobacterium tuberculosis (drug effects, growth & development, isolation & purification)
• Nitroimidazoles (administration & dosage, pharmacology, therapeutic use)
• Specific Pathogen-Free Organisms
• Spleen (microbiology)
• Tuberculosis, Multidrug-Resistant (drug therapy, microbiology)
• Tuberculosis, Pulmonary (drug therapy, microbiology)