Activity of 5-chloro-pyrazinamide in mice infected with Mycobacterium tuberculosis or Mycobacterium bovis

Zahoor Ahmad, Sandeep Tyagi, Austin Minkowski, Deepak Almeida, Eric L. Nuermberger, Kaitlin M. Peck, John T. Welch, Anthony S. Baughn, Williams R. Jacobs, Jacques H. Grosset

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background & objectives: Pyrazinamide is an essential component of first line anti-tuberculosis regimen as well as most of the second line regimens. This drug has a unique sterilizing activity against Mycobacterium tuberculosis. Its unique role in tuberculosis treatment has lead to the search and development of its structural analogues. One such analogue is 5-chloro-pyrazinamide (5-Cl-PZA) that has been tested under in vitro conditions against M. tuberculosis. The present study was designed with an aim to assess the activity of 5-Cl-PZA, alone and in combination with first-line drugs, against murine tuberculosis. Methods: The minimum inhibitory concentration (MIC) of 5-Cl-PZA in Middlebrook 7H9 broth (neutral pH) and the inhibitory titre of serum from mice that received a 300 mg/kg oral dose of 5-Cl-PZA 30min before cardiac puncture were determined. To test the tolerability of orally administered 5-Cl-PZA, uninfected mice received doses up to 300 mg/kg for 2 wk. Four weeks after low-dose aerosol infection either with M. tuberculosis or M. bovis, mice were treated 5 days/wk with 5-Cl-PZA, at doses ranging from 37.5 to 150 mg/kg, either alone or in combination with isoniazid and rifampicin. Antimicrobial activity was assessed by colony-forming unit counts in lungs after 4 and 8 wk of treatment. Results: The MIC of 5-Cl-PZA against M. tuberculosis was between 12.5 and 25 μg/ml and the serum inhibitory titre was 1:4. Under the same experimental conditions, the MIC of pyrazinamide was >100 μg/ ml and mouse serum had no inhibitory activity after a 300 mg/kg dose; 5-Cl-PZA was well tolerated in uninfected and infected mice up to 300 and 150 mg/kg, respectively. While PZA alone and in combination exhibited its usual antimicrobial activity in mice infected with M. tuberculosis and no activity in mice infected with M. bovis, 5-Cl-PZA exhibited antimicrobial activity neither in mice infected with M. tuberculosis nor in mice infected with M. bovis. Interpretation & conclusion: Our findings showed that 5-Cl-PZA at doses up to 150 mg/kg was not active in chronic murine TB model. Further studies need to be done to understand the mechanism and mode of inactivation in murine model of tuberculosis.

Original languageEnglish (US)
Pages (from-to)808-814
Number of pages7
JournalIndian Journal of Medical Research
Volume136
Issue number5
StatePublished - Nov 1 2012

Fingerprint

Pyrazinamide
Mycobacterium bovis
Mycobacterium tuberculosis
Tuberculosis
Microbial Sensitivity Tests
Serum
Isoniazid
Rifampin
Aerosols
Punctures
Pharmaceutical Preparations
Stem Cells

Keywords

  • Experimental chemotherapy
  • Mouse
  • Pyrazinamide
  • Tuberculosis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Ahmad, Z., Tyagi, S., Minkowski, A., Almeida, D., Nuermberger, E. L., Peck, K. M., ... Grosset, J. H. (2012). Activity of 5-chloro-pyrazinamide in mice infected with Mycobacterium tuberculosis or Mycobacterium bovis. Indian Journal of Medical Research, 136(5), 808-814.

Activity of 5-chloro-pyrazinamide in mice infected with Mycobacterium tuberculosis or Mycobacterium bovis. / Ahmad, Zahoor; Tyagi, Sandeep; Minkowski, Austin; Almeida, Deepak; Nuermberger, Eric L.; Peck, Kaitlin M.; Welch, John T.; Baughn, Anthony S.; Jacobs, Williams R.; Grosset, Jacques H.

In: Indian Journal of Medical Research, Vol. 136, No. 5, 01.11.2012, p. 808-814.

Research output: Contribution to journalArticle

Ahmad, Z, Tyagi, S, Minkowski, A, Almeida, D, Nuermberger, EL, Peck, KM, Welch, JT, Baughn, AS, Jacobs, WR & Grosset, JH 2012, 'Activity of 5-chloro-pyrazinamide in mice infected with Mycobacterium tuberculosis or Mycobacterium bovis', Indian Journal of Medical Research, vol. 136, no. 5, pp. 808-814.
Ahmad Z, Tyagi S, Minkowski A, Almeida D, Nuermberger EL, Peck KM et al. Activity of 5-chloro-pyrazinamide in mice infected with Mycobacterium tuberculosis or Mycobacterium bovis. Indian Journal of Medical Research. 2012 Nov 1;136(5):808-814.
Ahmad, Zahoor ; Tyagi, Sandeep ; Minkowski, Austin ; Almeida, Deepak ; Nuermberger, Eric L. ; Peck, Kaitlin M. ; Welch, John T. ; Baughn, Anthony S. ; Jacobs, Williams R. ; Grosset, Jacques H. / Activity of 5-chloro-pyrazinamide in mice infected with Mycobacterium tuberculosis or Mycobacterium bovis. In: Indian Journal of Medical Research. 2012 ; Vol. 136, No. 5. pp. 808-814.
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AU - Nuermberger, Eric L.

AU - Peck, Kaitlin M.

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