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

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.
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https://hal-u-picardie.archives-ouvertes.fr/hal-03592730
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Soumis le : mardi 1 mars 2022 - 15:13:22
Dernière modification le : jeudi 25 août 2022 - 11:48:28

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Jean-Philippe Lanoix, Thomas Ioerger, Aimee Ormond, Firat Kaya, James Sacchettini, et al.. Selective Inactivity of Pyrazinamide against Tuberculosis in C3HeB/FeJ Mice Is Best Explained by Neutral pH of Caseum. Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2016, 60 (2), pp.735-743. ⟨10.1128/AAC.01370-15⟩. ⟨hal-03592730⟩

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