ArticleACS infectious diseases2017
Pyrazinoic Acid Inhibits Mycobacterial Coenzyme A Biosynthesis by Binding to Aspartate Decarboxylase PanD.
Article in ACS infectious diseases, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 71 citations in OpenAlex.
- Fast-growing intracellular Mycobacterium tuberculosis populations evade antibiotic treatment.Nature communications · 2026Article
- Multidrug-resistant tuberculosis: a comprehensive review of pathogenesis, drug resistance, current treatment and future prospects.Archives of microbiology · 2026Review
- Predicting pyrazinamide resistance in Mycobacterium tuberculosis using a graph convolutional network.BMC microbiology · 2026Article
- Pyrazinamide killsbioRxiv : the preprint server for biology · 2025Article
- Nutritional Deficiencies and Management in Tuberculosis: Pharmacotherapeutic and Clinical Implications.Nutrients · 2025Review
- Article
- 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
- 3D Hydrogel Culture System Recapitulates Key Tuberculosis Phenotypes and Demonstrates Pyrazinamide Efficacy.Advanced healthcare materials · 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
- Drug Susceptibility and Mutation Profiles in Mycobacterium tuberculosis Isolates from a Tertiary Care Hospital in Kerala, India.The American journal of tropical medicine and hygiene · 2024Article
- Prevalence, Transmission and Genetic Diversity of Pyrazinamide Resistance Among Multidrug-ResistantInfection and drug resistance · 2024Article
- Review
- 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
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- Cephem-Pyrazinoic Acid Conjugates: Circumventing Resistance in Mycobacterium tuberculosis.Chemistry (Weinheim an der Bergstrasse, Germany) · 2022Article
- Structural and Mechanistic Insights intoACS infectious diseases · 2022Article
- Structural and Dynamic Insights into the W68L, L85P, and T87A Mutations ofInternational journal of environmental research and public health · 2022Article
- Pantothenate and CoA biosynthesis in Apicomplexa and their promise as antiparasitic drug targets.PLoS pathogens · 2021Review
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
Previously, we showed that a major in vitro and in vivo mechanism of resistance to pyrazinoic acid (POA), the bioactive component of the critical tuberculosis (TB) prodrug pyrazinamide (PZA), involves missense mutations in the aspartate decarboxylase PanD, an enzyme required for coenzyme A biosynthesis. What is the mechanism of action of POA? Upon demonstrating that treatment of M. bovis BCG with POA resulted in a depletion of intracellular coenzyme A and confirming that this POA-mediated depletion is prevented by either missense mutations in PanD or exogenous supplementation of pantothenate, we hypothesized that POA binds to PanD and that this binding blocks the biosynthetic pathway. Here, we confirm both hypotheses. First, metabolomic analyses showed that POA treatment resulted in a reduction of the concentrations of all coenzyme A precursors downstream of the PanD-mediated catalytic step. Second, using isothermal titration calorimetry, we established that POA, but not its prodrug PZA, binds to PanD. Binding was abolished for mutant PanD proteins. Taken together, these findings support a mechanism of action of POA in which the bioactive component of PZA inhibits coenzyme A biosynthesis via binding to aspartate decarboxylase PanD. Together with previous works, these results establish PanD as a genetically, metabolically, and biophysically validated target of PZA.
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