Impact of immunopathology on the antituberculous activity of pyrazinamide.
Landry Blanc, Jansy Passiflora Sarathy, Nadine Alvarez Cabrera, Paul O'Brien, Isabela Dias-Freedman, Marizel Mina, James Sacchettini, Radojka M Savic, Martin Gengenbacher, Brendan K Podell, Brendan Prideaux, Thomas Ioerger, Thomas Dick, Véronique Dartois
Author Information
Landry Blanc: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ.
Jansy Passiflora Sarathy: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ.
Nadine Alvarez Cabrera: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ.
Paul O'Brien: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ.
Isabela Dias-Freedman: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ. ORCID
Marizel Mina: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ.
James Sacchettini: Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX. ORCID
Radojka M Savic: Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, San Francisco, CA.
Martin Gengenbacher: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ. ORCID
Brendan K Podell: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO.
Brendan Prideaux: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ. ORCID
Thomas Ioerger: Department of Computer Science, Texas A&M University, College Station, TX.
Thomas Dick: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ. ORCID
Véronique Dartois: Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ veronique.dartois@rutgers.edu. ORCID
In the 1970s, inclusion of pyrazinamide (PZA) in the drug regimen of tuberculosis (TB) patients for the first 2 mo achieved a drastic reduction of therapy duration. Until now, however, the mechanisms underlying PZA's unique contribution to efficacy have remained controversial, and animal efficacy data vary across species. To understand how PZA kills bacterial populations present in critical lung lesion compartments, we first characterized a rabbit model of active TB, showing striking similarities in lesion types and fates to nonhuman primate models deemed the most appropriate surrogates of human TB. We next employed this model with lesion-centric molecular and bacteriology readouts to demonstrate that PZA exhibits potent activity against residing in difficult-to-sterilize necrotic lesions. Our data also indicate that PZA is slow acting, suggesting that PZA administration beyond the first 2 mo may accelerate the cure. In conclusion, we provide a pharmacodynamic explanation for PZA's treatment-shortening effect and deliver new tools to dissect the contribution of immune response versus drug at the lesion level.
Associated Data
RefSeq | NZ_CM001043.1
References
Antimicrob Agents Chemother. 2018 Jan 25;62(2):null
[PMID: 29203492]
