title: Activity of 5-chloro-pyrazinamide in mice infected with Mycobacterium tuberculosis or Mycobacterium bovis.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Zahoor
authors.initials: Z
authors.lastname: Ahmad
authors.forename: Sandeep
authors.initials: S
authors.lastname: Tyagi
authors.forename: Austin
authors.initials: A
authors.lastname: Minkowsk
authors.forename: Deepak
authors.initials: D
authors.lastname: Almeida
authors.forename: Eric L
authors.initials: EL
authors.lastname: Nuermberger
authors.forename: Kaitlin M
authors.initials: KM
authors.lastname: Peck
authors.forename: John T
authors.initials: JT
authors.lastname: Welch
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Baughn
authors.forename: Williams R
authors.initials: WR
authors.lastname: Jacobs
authors.forename: Jacques H
authors.initials: JH
authors.lastname: Grosset
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009163:Mycobacterium bovis / Q000187:drug effects* / Q000302:isolation & purification; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000302:isolation & purification; D011718:Pyrazinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology
chemical_list: C111084:5-chloropyrazinamide; D000995:Antitubercular Agents; D011718:Pyrazinamide