Selective Inactivity of Pyrazinamide against Tuberculosis in C3HeB/FeJ Mice Is Best Explained by Neutral pH of Caseum

Antimicrob Agents Chemother. 2015 Nov 16;60(2):735-43. doi: 10.1128/AAC.01370-15. Print 2016 Feb.


Pyrazinamide (PZA) is one of only two sterilizing drugs in the first-line antituberculosis regimen. Its activity is strongly pH dependent; the MIC changes by several orders of magnitude over a range of pH values that may be encountered in various in vivo compartments. We recently reported selective inactivity of PZA in a subset of C3HeB/FeJ mice with large caseous lung lesions. In the present study, we evaluated whether such inactivity was explained by poor penetration of PZA into such lesions or selection of drug-resistant mutants. Despite demonstrating similar dose-proportional PZA exposures in plasma, epithelial lining fluid, and lung lesions, no dose response was observed in a subset of C3HeB/FeJ mice with the highest CFU burden. Although PZA-resistant mutants eventually replaced the susceptible bacilli in BALB/c mice and in C3HeB/FeJ mice with low total CFU burdens, they never exceeded 1% of the total population in nonresponding C3HeB/FeJ mice. The selective inactivity of PZA in large caseous lesions of C3HeB/FeJ mice is best explained by the neutral pH of liquefying caseum.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitubercular Agents / therapeutic use*
  • Disease Models, Animal
  • Drug Resistance, Bacterial / physiology*
  • Genome, Bacterial / genetics
  • Hydrogen-Ion Concentration
  • Lung / microbiology
  • Lung / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Microbial Sensitivity Tests
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / genetics
  • Pyrazinamide / therapeutic use*
  • Tuberculosis, Pulmonary / drug therapy*


  • Antitubercular Agents
  • Pyrazinamide