ArticlePloS one2012
High-throughput screening and sensitized bacteria identify an M. tuberculosis dihydrofolate reductase inhibitor with whole cell activity.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
What it found
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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.
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Who cites it
26 citing papers in PubMed, 54 citations in OpenAlex.
- Thiadiazole-azetidinone sulfonamide hybrids with antimycobacterial activity supported by structure-based analysis.RSC advances · 2026Article
- Pharmacological validation of dihydrofolate reductase as a drug target inAntimicrobial agents and chemotherapy · 2024Article
- Selective Non-toxics Inhibitors Targeting DHFR for Tuberculosis and Cancer Therapy: Pharmacophore Generation and Molecular Dynamics Simulation.Bioinformatics and biology insights · 2023Article
- Potency boost of aProceedings of the National Academy of Sciences of the United States of America · 2021Article
- Identification of P218 as a potent inhibitor ofRSC medicinal chemistry · 2021Article
- Discovery of Selective Toxoplasma gondii Dihydrofolate Reductase Inhibitors for the Treatment of Toxoplasmosis.Journal of medicinal chemistry · 2019Article
- Innovation in neglected tropical disease drug discovery and development.Infectious diseases of poverty · 2018Review
- Hit Generation in TB Drug Discovery: From Genome to Granuloma.Chemical reviews · 2018Review
- Antimycobacterial Metabolism: Illuminating Mycobacterium tuberculosis Biology and Drug Discovery.Trends in microbiology · 2017Review
- Review
- A Target-Based Whole Cell Screen Approach To Identify Potential Inhibitors of Mycobacterium tuberculosis Signal Peptidase.ACS infectious diseases · 2016Article
- Discovery of Potent and Selective Leads againstACS medicinal chemistry letters · 2016Article
- Therapeutic Potential of the Mycobacterium tuberculosis Mycolic Acid Transporter, MmpL3.Antimicrobial agents and chemotherapy · 2016Article
- dfrA thyA Double Deletion in para-Aminosalicylic Acid-Resistant Mycobacterium tuberculosis Beijing Strains.Antimicrobial agents and chemotherapy · 2016Article
- Avoiding Fluorescence Assay Interference-The Case for Diaphorase.Assay and drug development technologies · 2016Review
- Propargyl-Linked Antifolates Are Potent Inhibitors of Drug-Sensitive and Drug-Resistant Mycobacterium tuberculosis.PloS one · 2016Article
- A Focused Screen Identifies Antifolates with Activity on Mycobacterium tuberculosis.ACS infectious diseases · 2015Article
- The identification of novel Mycobacterium tuberculosis DHFR inhibitors and the investigation of their binding preferences by using molecular modelling.Scientific reports · 2015Article
- Mycobacterium tuberculosis folate metabolism and the mechanistic basis for para-aminosalicylic acid susceptibility and resistance.Antimicrobial agents and chemotherapy · 2015Review
- Genetic Approaches to Facilitate Antibacterial Drug Development.Cold Spring Harbor perspectives in medicine · 2015Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is a bacterial pathogen that claims roughly 1.4 million lives every year. Current drug regimens are inefficient at clearing infection, requiring at least 6 months of chemotherapy, and resistance to existing agents is rising. There is an urgent need for new drugs that are more effective and faster acting. The folate pathway has been successfully targeted in other pathogens and diseases, but has not yielded a lead drug against tuberculosis. We developed a high-throughput screening assay against Mtb dihydrofolate reductase (DHFR), a critical enzyme in the folate pathway, and screened a library consisting of 32,000 synthetic and natural product-derived compounds. One potent inhibitor containing a quinazoline ring was identified. This compound was active against the wild-type laboratory strain H37Rv (MIC(99) = 207 µM). In addition, an Mtb strain with artificially lowered DHFR levels showed increased sensitivity to this compound (MIC(99) = 70.7 µM), supporting that the inhibition was target-specific. Our results demonstrate the potential to identify Mtb DHFR inhibitors with activity against whole cells, and indicate the power of using a recombinant strain of Mtb expressing lower levels of DHFR to facilitate the discovery of antimycobacterial agents. With these new tools, we highlight the folate pathway as a potential target for new drugs to combat the tuberculosis epidemic.
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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.