ArticleEmerging microbes & infections2014
Aspartate decarboxylase (PanD) as a new target of pyrazinamide in Mycobacterium tuberculosis.
Article in Emerging microbes & infections, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 88 papers, 1 of them a synthesis that pooled it.
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Who cites it
88 citing papers in PubMed, 1 synthesis or guideline pooled it, 147 citations in OpenAlex.
- A Global Perspective on Pyrazinamide Resistance: Systematic Review and Meta-Analysis.PloS one · 2015Pooled it
- TargetingACS omega · 2026Article
- The epidemiology and gene mutation characteristics of pyrazinamide-resistantEmerging microbes & infections · 2025Article
- Isoleucyl-tRNA synthetase depletion reveals vulnerabilities in Mycobacterium abscessus and Mycobacterium marinum.Communications biology · 2025Article
- Pyrazinamide killsbioRxiv : the preprint server for biology · 2025Article
- Investigating the Mechanism of Antimycobacterial and Antiproliferative Activity of (E)-N'-Benzylidenepyrazine-2-Carbohydrazides and their Derivatives.ChemMedChem · 2025Article
- Chemical genetic interactions elucidate pathways controlling tuberculosis antibiotic efficacy during infection.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Synthesis, Docking, and Biological Studies of Pyrazine Derivatives as Antimycobacterial Agents.Medicinal chemistry (Shariqah (United Arab Emirates)) · 2025Article
- Determining the minimum inhibitory concentrations of pyrazinamide againstFrontiers in microbiology · 2025Article
- Prevalence and Clinical Implications of Pyrazinamide Resistance in Newly Diagnosed TB Patients in Uganda.Infection and drug resistance · 2025Article
- Oxidative stress drives potent bactericidal activity of pyrazinamide againstbioRxiv : the preprint server for biology · 2024Article
- Bacterial persisters: molecular mechanisms and therapeutic development.Signal transduction and targeted therapy · 2024Review
- Metabolic Rewiring ofMetabolites · 2024Review
- Studying the dynamics of the drug processing of pyrazinamide in Mycobacterium tuberculosis.PloS one · 2024Article
- Pyrazinoic acid, the active form of the anti-tuberculosis drug pyrazinamide, and aromatic carboxylic acid analogs are protonophores.Frontiers in molecular biosciences · 2024Article
- Review
- Structure activity relationship of pyrazinoic acid analogs as potential antimycobacterial agents.Bioorganic & medicinal chemistry · 2022Article
- Computer-Based Identification of Potential Druggable Targets in Multidrug-ResistantMicroorganisms · 2022Article
- Superior Efficacy of a TBI-166, Bedaquiline, and Pyrazinamide Combination Regimen in a Murine Model of Tuberculosis.Antimicrobial agents and chemotherapy · 2022Article
- Structural and Mechanistic Insights intoACS infectious diseases · 2022Article
28 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Pyrazinamide (PZA) is a frontline anti-tuberculosis drug that plays a crucial role in the treatment of both drug-susceptible and multidrug-resistant tuberculosis (MDR-TB). PZA is a prodrug that is converted to its active form, pyrazinoic acid (POA), by a nicotinamidase/pyrazinamidase encoded by the pncA gene, the mutation of which is the major cause of PZA resistance. Although RpsA (ribosomal protein S1, involved in trans-translation) has recently been shown to be a target of POA/PZA, whole-genome sequencing has identified mutations in the panD gene encoding aspartate decarboxylase in PZA-resistant strains lacking pncA and rpsA mutations. To gain more insight into a possible new target of PZA, we isolated 30 POA-resistant mutants lacking mutations in pncA and rpsA from M. tuberculosis in vitro, and whole-genome sequencing of 3 mutants identified various mutations in the panD gene. Additionally, sequencing analysis revealed that the remaining 27 POA-resistant mutants all harbored panD mutations affecting the C-terminus of the PanD protein, with PanD M117I being the most frequent mutation (24/30, 80%). Conditional overexpression of panD from M. tuberculosis, M. smegmatis or E. coli, or of M. tuberculosis mutant PanD M117I, all conferred resistance to POA and PZA in M. tuberculosis. β-alanine and pantothenate, which are downstream products of PanD, were found to antagonize the antituberculosis activity of POA. In addition, the activity of the M. tuberculosis PanD enzyme was inhibited by POA at therapeutically relevant concentrations in a concentration-dependent manner but was not inhibited by the prodrug PZA or the control compound nicotinamide. These findings suggest that PanD represents a new target of PZA/POA. These results have implications for a better understanding of this peculiar persister drug and for the design of new drugs targeting M. tuberculosis persisters for improved treatment.
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