Selective inactivity of pyrazinamide against tuberculosis in C3HeB/FeJ mice is best explained by neutral pH of caseum

Jean Philippe Lanoix, Thomas Ioerger, Aimee Ormond, Firat Kaya, James Sacchettini, Véronique Dartois, Eric Nuermberger

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)735-743
Number of pages9
JournalAntimicrobial agents and chemotherapy
Volume60
Issue number2
DOIs
StatePublished - Feb 2016

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ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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