ArticleACS infectious diseases2015
Host-Mediated Bioactivation of Pyrazinamide: Implications for Efficacy, Resistance, and Therapeutic Alternatives.
Article in ACS infectious diseases, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
52 citing papers in PubMed, 77 citations in OpenAlex.
- Coadministration of Allopurinol To Increase Antimycobacterial Efficacy of Pyrazinamide as Evaluated in a Whole-Blood Bactericidal Activity Model.Antimicrobial agents and chemotherapy · 2017Trial
- Essential role of MHC II in the antitubercular efficacy of pyrazinamide.Antimicrobial agents and chemotherapy · 2026Article
- Novel Prodrug Strategies for the Treatment of Tuberculosis.Chemistry, an Asian journal · 2024Review
- TargetingMicrobiology (Reading, England) · 2024Review
- Clinical Significance of Preoperative Pyrazinamide-Containing Therapy in Tuberculous Constrictive Pericarditis.Infection and drug resistance · 2024Article
- Pharmacokinetic Considerations for Optimizing Inhaled Spray-Dried Pyrazinoic Acid Formulations.Molecular pharmaceutics · 2023Article
- Antibiotic-Derived Radiotracers for Positron Emission Tomography: Nuclear or "Unclear" Infection Imaging?Angewandte Chemie (International ed. in English) · 2022Review
- Interleukin-13-Overexpressing Mice Represent an Advanced Preclinical Model for Detecting the Distribution of Antimycobacterial Drugs within Centrally Necrotizing Granulomas.Antimicrobial agents and chemotherapy · 2022Article
- No implication of HIV coinfection on the plasma exposure to rifampicin, pyrazinamide, and ethambutol in tuberculosis patients.Clinical and translational science · 2022Article
- Metabolism and Hepatotoxicity of Pyrazinamide, an Antituberculosis Drug.Drug metabolism and disposition: the biological fate of chemicals · 2021Review
- Factors Affecting the Pharmacokinetics of Pyrazinamide and Its Metabolites in Patients Coinfected with HIV and Implications for Individualized Dosing.Antimicrobial agents and chemotherapy · 2021Article
- Article
- Development of New Tuberculosis Drugs: Translation to Regimen Composition for Drug-Sensitive and Multidrug-Resistant Tuberculosis.Annual review of pharmacology and toxicology · 2021Review
- The Bewildering Antitubercular Action of Pyrazinamide.Microbiology and molecular biology reviews : MMBR · 2020Review
- Direct Determination of Pyrazinamide (PZA) Susceptibility by Sputum Microscopic Observation Drug Susceptibility (MODS) Culture at Neutral pH: the MODS-PZA Assay.Journal of clinical microbiology · 2020Article
- Article
- Immunological detection of pyrazine-2-carboxylic acid for the detection of pyrazinamide resistance in Mycobacterium tuberculosis.PloS one · 2020Article
- Vitamin in the Crosshairs: Targeting Pantothenate and Coenzyme A Biosynthesis for New Antituberculosis Agents.Frontiers in cellular and infection microbiology · 2020Review
- Pharmacological and Molecular Mechanisms Behind the Sterilizing Activity of Pyrazinamide.Trends in pharmacological sciences · 2019Review
- Impact of the host environment on the antitubercular action of pyrazinamide.EBioMedicine · 2019Review
Corrections and comments
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Authors and funding
21 authors at 11 institutions in 3 countries.
Funding
Abstract
Pyrazinamide has played a critical role in shortening therapy against drug-sensitive, drug-resistant, active, and latent tuberculosis (TB). Despite widespread recognition of its therapeutic importance, the sterilizing properties of this 60-year-old drug remain an enigma given its rather poor activity in vitro. Here we revisit longstanding paradigms and offer pharmacokinetic explanations for the apparent disconnect between in vitro activity and clinical impact. We show substantial host-mediated conversion of prodrug pyrazinamide (PZA) to the active form, pyrazinoic acid (POA), in TB patients and in animal models. We demonstrate favorable penetration of this pool of circulating POA from plasma into lung tissue and granulomas, where the pathogen resides. In standardized growth inhibition experiments, we show that POA exhibits superior in vitro potency compared to PZA, indicating that the vascular supply of host-derived POA may contribute to the in vivo efficacy of PZA, thereby reducing the apparent discrepancy between in vitro and in vivo activity. However, the results also raise the possibility that subinhibitory concentrations of POA generated by the host could fuel the emergence of resistance to both PZA and POA. In contrast to widespread expectations, we demonstrate good oral bioavailability and exposure in preclinical species in pharmacokinetic studies of oral POA. Baseline exposure of oral POA can be further increased by the xanthine oxidase inhibitor and approved gout drug allopurinol. These promising results pave the way for clinical investigations of oral POA as a therapeutic alternative or an add-on to overcome PZA resistance and salvage this essential TB drug.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.