ArticleACS infectious diseases2016
Pyrazinamide Resistance Is Caused by Two Distinct Mechanisms: Prevention of Coenzyme A Depletion and Loss of Virulence Factor Synthesis.
Article in ACS infectious diseases, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
61 citing papers in PubMed, 92 citations in OpenAlex.
- A Case of Transmission of Bedaquiline- and Linezolid-Resistant Tuberculosis.International journal of molecular sciences · 2026Article
- Uncovering resistance pathways to first- and last-line antibiotics inMicrobial genomics · 2026Article
- Article
- Article
- Pyrazinamide killsbioRxiv : the preprint server for biology · 2025Article
- Article
- Antitubercular potential and pH-driven mode of action of salicylic acid derivatives.FEBS open bio · 2025Article
- Enhancing diagnostic efficiency of pyrazinamide resistance inCurrent research in microbial sciences · 2025Article
- Determining the minimum inhibitory concentrations of pyrazinamide againstFrontiers in microbiology · 2025Article
- Propionate prevents loss of the PDIM virulence lipid in Mycobacterium tuberculosis.Nature microbiology · 2024Article
- TargetingMicrobiology (Reading, England) · 2024Review
- Prediction of pyrazinamide resistance inJAC-antimicrobial resistance · 2024Article
- Inhibition of host PARP1 contributes to the anti-inflammatory and antitubercular activity of pyrazinamide.Nature communications · 2023Article
- The PDIM paradox ofbioRxiv : the preprint server for biology · 2023Article
- Pharmacokinetic Considerations for Optimizing Inhaled Spray-Dried Pyrazinoic Acid Formulations.Molecular pharmaceutics · 2023Article
- PROTAC antibiotics: the time is now.Expert opinion on drug discovery · 2023Article
- Galleria mellonella-intracellular bacteria pathogen infection models: the ins and outs.FEMS microbiology reviews · 2023Review
- Bacillus Calmette-Guérin Spondylodiscitis after Intravesical BCG Therapy: A Case Report.Spine surgery and related research · 2022Article
- Structure activity relationship of pyrazinoic acid analogs as potential antimycobacterial agents.Bioorganic & medicinal chemistry · 2022Article
- Mutations Associated with Pyrazinamide Resistance in Mycobacterium tuberculosis: A Review and Update.Current microbiology · 2022Review
1 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
Pyrazinamide (PZA) is a critical component of first- and second-line treatments of tuberculosis (TB), yet its mechanism of action largely remains an enigma. We carried out a genetic screen to isolate Mycobacterium bovis BCG mutants resistant to pyrazinoic acid (POA), the bioactive derivative of PZA, followed by whole genome sequencing of 26 POA resistant strains. Rather than finding mutations in the proposed candidate targets fatty acid synthase I and ribosomal protein S1, we found resistance conferring mutations in two pathways: missense mutations in aspartate decarboxylase panD, involved in the synthesis of the essential acyl carrier coenzyme A (CoA), and frameshift mutations in the vitro nonessential polyketide synthase genes mas and ppsA-E, involved in the synthesis of the virulence factor phthiocerol dimycocerosate (PDIM). Probing for cross resistance to two structural analogs of POA, nicotinic acid and benzoic acid, showed that the analogs share the PDIM- but not the CoA-related mechanism of action with POA. We demonstrated that POA depletes CoA in wild-type bacteria, which is prevented by mutations in panD. Sequencing 10 POA-resistant Mycobacterium tuberculosis H37Rv isolates confirmed the presence of at least 2 distinct mechanisms of resistance to the drug. The emergence of resistance through the loss of a virulence factor in vitro may explain the lack of clear molecular patterns in PZA-resistant clinical isolates, other than mutations in the prodrug-converting enzyme. The apparent interference of POA with virulence pathways may contribute to the drug's excellent in vivo efficacy compared to its modest in vitro potency.
Indexed as
Identifiers
What OpenQuestion holds
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.