ArticleProceedings of the National Academy of Sciences of the United States of America2006
Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium tuberculosis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 165 papers, 1 of them a synthesis that pooled it.
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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
165 citing papers in PubMed, 1 synthesis or guideline pooled it, 330 citations in OpenAlex.
- Systematic review of mutations associated with resistance to the new and repurposed Mycobacterium tuberculosis drugs bedaquiline, clofazimine, linezolid, delamanid and pretomanid.The Journal of antimicrobial chemotherapy · 2020Pooled it
- Safety, tolerability, and pharmacokinetics of PA-824 in healthy subjects.Antimicrobial agents and chemotherapy · 2009Trial
- Targeting Latent Tuberculosis Using Hypoxia-Activated Prodrugs of Bedaquiline Analogues.ACS medicinal chemistry letters · 2026Article
- Exploiting DprE2 pathway redundancy to enhance potency and overcome resistance to pretomanid in Mycobacterium tuberculosis.npj antimicrobials and resistance · 2026Article
- High-throughput characterization of Mycobacterium tuberculosis gene function across diverse conditions.PLoS biology · 2026Article
- Article
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- Editorial: Vaccines and molecular therapeutics for tuberculosis.Frontiers in immunology · 2026Article
- Pretomanid for the treatment of drug resistant pulmonary tuberculosis: a comprehensive review.Archives of microbiology · 2025Review
- Defining the mechanism of action of the nitrofuranyl piperazine HC2210 against Mycobacterium abscessus.npj antimicrobials and resistance · 2025Article
- Functions of nitroreductases in mycobacterial physiology and drug susceptibility.Journal of bacteriology · 2025Review
- Pharmacology of emerging drugs for the treatment of multi-drug resistant tuberculosis.Journal of clinical tuberculosis and other mycobacterial diseases · 2024Review
- CRISPR Screening and Comparative LC-MS Analysis Identify Genes Mediating Efficacy of Delamanid and Pretomanid against Mycobacterium tuberculosis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Propionate prevents loss of the PDIM virulence lipid in Mycobacterium tuberculosis.Nature microbiology · 2024Article
- Combating antimicrobial resistance in malaria, HIV and tuberculosis.Nature reviews. Drug discovery · 2024Review
- Prevalence and genetic basis of Mycobacterium tuberculosis resistance to pretomanid in China.Annals of clinical microbiology and antimicrobials · 2024Article
- Antitubercular drugs: possible role of natural products acting as antituberculosis medication in overcoming drug resistance and drug-induced hepatotoxicity.Naunyn-Schmiedeberg's archives of pharmacology · 2024Review
- Identification and optimization of pyridine carboxamide-based scaffold as a drug lead forAntimicrobial agents and chemotherapy · 2024Article
- TheMicrobiology spectrum · 2024Article
- Recent Biochemical Advances in Antitubercular Drugs: Challenges and Future.Current topics in medicinal chemistry · 2024Review
105 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
PA-824 is a promising new compound for the treatment of tuberculosis that is currently undergoing human trials. Like its progenitors metronidazole and CGI-17341, PA-824 is a prodrug of the nitroimidazole class, requiring bioreductive activation of an aromatic nitro group to exert an antitubercular effect. We have confirmed that resistance to PA-824 (a nitroimidazo-oxazine) and CGI-17341 (a nitroimidazo-oxazole) is most commonly mediated by loss of a specific glucose-6-phosphate dehydrogenase (FGD1) or its deazaflavin cofactor F420, which together provide electrons for the reductive activation of this class of molecules. Although FGD1 and F420 are necessary for sensitivity to these compounds, they are not sufficient and require additional accessory proteins that directly interact with the nitroimidazole. To understand more proximal events in the reductive activation of PA-824, we examined mutants that were wild-type for both FGD1 and F420 and found that, although these mutants had acquired high-level resistance to PA-824 (and another nitroimidazo-oxazine), they retained sensitivity to CGI-17341 (and a related nitroimidazo-oxazole). Microarray-based comparative genome sequencing of these mutants identified lesions in Rv3547, a conserved hypothetical protein with no known function. Complementation with intact Rv3547 fully restored sensitivity to nitroimidazo-oxazines and restored the ability of Mtb to metabolize PA-824. These results suggest that the sensitivity of Mtb to PA-824 and related compounds is mediated by a protein that is highly specific for subtle structural variations in these bicyclic nitroimidazoles.
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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.