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

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 30 min 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.

• Authors: Zahoor Ahmad, Sandeep Tyagi, Austin Minkowsk, Deepak Almeida, Eric L Nuermberger, Kaitlin M Peck, John T Welch, Anthony S Baughn, Williams R Jacobs Jr, Jacques H Grosset
• Journal: The Indian journal of medical research (Indian J Med Res) Vol. 136 Issue 5 Pg. 808-14 (Nov 2012) ISSN: 0971-5916 [Print] India
• PMID: 23287128 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 5-chloropyrazinamide
• Antitubercular Agents
• Pyrazinamide

Topics

• Animals
• Antitubercular Agents (pharmacology, therapeutic use)
• Female
• Mice
• Mice, Inbred BALB C
• Microbial Sensitivity Tests
• Mycobacterium bovis (drug effects, isolation & purification)
• Mycobacterium tuberculosis (drug effects, isolation & purification)
• Pyrazinamide (analogs & derivatives, therapeutic use)
• Tuberculosis (drug therapy, microbiology)