Selective Inactivity of Pyrazinamide against Tuberculosis in C3HeB/FeJ Mice Is Best Explained by Neutral pH of Caseum
Year: 2015
Type: article
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.
DOI: 10.1128/aac.01370-15
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: Johns Hopkins University - to validate a new mouse model resembling human pathology for tuberculosis drug development, G2483435703, Rutgers, The State University of New Jersey - to enable the discovery of effective drug regimens for drug sensitive and drug resistant tuberculosis (TB) disease, by integrating plasma and lesio..., Target based discovery of next generation pyrazinamide, The Johns Hopkins Center for AIDS Research (JHU CFAR)
OpenAlex ID: W2175339748