ArticleThe Journal of biological chemistry2013
para-Aminosalicylic acid is a prodrug targeting dihydrofolate reductase in Mycobacterium tuberculosis.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 91 papers, 1 of them a synthesis that pooled it.
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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
91 citing papers in PubMed, 1 synthesis or guideline pooled it, 191 citations in OpenAlex.
- Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline.American journal of respiratory and critical care medicine · 2019Guideline
- Pharmacokinetics of para-aminosalicylic acid in HIV-uninfected and HIV-coinfected tuberculosis patients receiving antiretroviral therapy, managed for multidrug-resistant and extensively drug-resistant tuberculosis.Antimicrobial agents and chemotherapy · 2014Trial
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- The Adverse Effects of Tuberculosis Treatment: A Comprehensive Literature Review.Medicina (Kaunas, Lithuania) · 2025Review
- Antitubercular potential and pH-driven mode of action of salicylic acid derivatives.FEBS open bio · 2025Article
- The T120P or M172V mutation onEmerging microbes & infections · 2024Article
- Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active againstJournal of medicinal chemistry · 2024Article
- Plant-Derived Antimicrobials and Their Crucial Role in Combating Antimicrobial Resistance.Antibiotics (Basel, Switzerland) · 2024Review
- The Lreu_1276 protein fromApplied and environmental microbiology · 2024Article
- Integrating bacterial molecular genetics with chemical biology for renewed antibacterial drug discovery.The Biochemical journal · 2024Review
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- The aminosalicylate - folate connection.Drug metabolism reviews · 2024Review
- Pharmacological validation of dihydrofolate reductase as a drug target inAntimicrobial agents and chemotherapy · 2024Article
- Pyrazinoic acid, the active form of the anti-tuberculosis drug pyrazinamide, and aromatic carboxylic acid analogs are protonophores.Frontiers in molecular biosciences · 2024Article
- A machine-learning based model for automated recommendation of individualized treatment of rifampicin-resistant tuberculosis.PloS one · 2024Article
- Competition between HAntibiotics (Basel, Switzerland) · 2023Article
- New nitazoxanide derivatives: design, synthesis, biological evaluation, and molecular docking studies as antibacterial and antimycobacterial agents.RSC medicinal chemistry · 2023Article
31 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
12 authors at 5 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
para-Aminosalicylic acid (PAS) is one of the antimycobacterial drugs currently used for multidrug-resistant tuberculosis. Although it has been in clinical use for over 60 years, its mechanism(s) of action remains elusive. Here we report that PAS is a prodrug targeting dihydrofolate reductase (DHFR) through an unusual and novel mechanism of action. We provide evidences that PAS is incorporated into the folate pathway by dihydropteroate synthase (DHPS) and dihydrofolate synthase (DHFS) to generate a hydroxyl dihydrofolate antimetabolite, which in turn inhibits DHFR enzymatic activity. Interestingly, PAS is recognized by DHPS as efficiently as its natural substrate para-amino benzoic acid. Chemical inhibition of DHPS or mutation in DHFS prevents the formation of the antimetabolite, thereby conferring resistance to PAS. In addition, we identified a bifunctional enzyme (riboflavin biosynthesis protein (RibD)), a putative functional analog of DHFR in a knock-out strain. This finding is further supported by the identification of PAS-resistant clinical isolates encoding a RibD overexpression mutation displaying cross-resistance to genuine DHFR inhibitors. Our findings reveal that a metabolite of PAS inhibits DHFR in the folate pathway. RibD was shown to act as a functional analog of DHFR, and as for DHFS, both were shown to be associated in PAS resistance in laboratory strains and clinical isolates.
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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.