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Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models.
Antimicrob Agents Chemother. 2005 Jun; 49(6):2294-301.AA

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+Show Affiliations

Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA. lenaerts@colostate.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15917524

Citation

Lenaerts, Anne J., et al. "Preclinical Testing of the Nitroimidazopyran PA-824 for Activity Against Mycobacterium Tuberculosis in a Series of in Vitro and in Vivo Models." Antimicrobial Agents and Chemotherapy, vol. 49, no. 6, 2005, pp. 2294-301.
Lenaerts AJ, Gruppo V, Marietta KS, et al. Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models. Antimicrob Agents Chemother. 2005;49(6):2294-301.
Lenaerts, A. J., Gruppo, V., Marietta, K. S., Johnson, C. M., Driscoll, D. K., Tompkins, N. M., Rose, J. D., Reynolds, R. C., & Orme, I. M. (2005). Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models. Antimicrobial Agents and Chemotherapy, 49(6), 2294-301.
Lenaerts AJ, et al. Preclinical Testing of the Nitroimidazopyran PA-824 for Activity Against Mycobacterium Tuberculosis in a Series of in Vitro and in Vivo Models. Antimicrob Agents Chemother. 2005;49(6):2294-301. PubMed PMID: 15917524.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models. AU - Lenaerts,Anne J, AU - Gruppo,Veronica, AU - Marietta,Karen S, AU - Johnson,Christine M, AU - Driscoll,Diane K, AU - Tompkins,Nicholas M, AU - Rose,Jerry D, AU - Reynolds,Robert C, AU - Orme,Ian M, PY - 2005/5/27/pubmed PY - 2005/7/27/medline PY - 2005/5/27/entrez SP - 2294 EP - 301 JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. VL - 49 IS - 6 N2 - 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. SN - 0066-4804 UR - https://www.unboundmedicine.com/medline/citation/15917524/Preclinical_testing_of_the_nitroimidazopyran_PA_824_for_activity_against_Mycobacterium_tuberculosis_in_a_series_of_in_vitro_and_in_vivo_models_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&amp;pmid=15917524 DB - PRIME DP - Unbound Medicine ER -