ArticleProceedings of the National Academy of Sciences of the United States of America2013
Diarylcoumarins inhibit mycolic acid biosynthesis and kill Mycobacterium tuberculosis by targeting FadD32.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. 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, 95 citations in OpenAlex.
- Exploring the Potential of Coumarin as a Potent Antitubercular Agent.Mini reviews in medicinal chemistry · 2026Review
- 3-Hydroxykynurenine targets kainate receptors to promote defense against infection.Nature chemical biology · 2024Article
- Diving into drug-screening: zebrafish embryos as an in vivo platform for antimicrobial drug discovery and assessment.FEMS microbiology reviews · 2024Review
- Structural basis for the development of potential inhibitors targeting FadD23 from Mycobacterium tuberculosis.Acta crystallographica. Section F, Structural biology communications · 2023Article
- PatA Regulates Isoniazid Resistance by Mediating Mycolic Acid Synthesis and Controls Biofilm Formation by Affecting Lipid Synthesis in Mycobacteria.Microbiology spectrum · 2023Article
- Tuberculosis: Pathogenesis, Current Treatment Regimens and New Drug Targets.International journal of molecular sciences · 2023Review
- OvercomingActa pharmaceutica Sinica. B · 2022Review
- Identification of cell wall synthesis inhibitors active against Mycobacterium tuberculosis by competitive activity-based protein profiling.Cell chemical biology · 2022Article
- A Coumarin-Based Analogue of Thiacetazone as Dual Covalent Inhibitor and Potential Fluorescent Label of HadA inACS infectious diseases · 2021Article
- Antibiotics and resistance: the two-sided coin of the mycobacterial cell wall.Cell surface (Amsterdam, Netherlands) · 2020Review
- Development of small-molecule inhibitors of fatty acyl-AMP and fatty acyl-CoA ligases in Mycobacterium tuberculosis.European journal of medicinal chemistry · 2020Article
- SAR Analysis of Small Molecules Interfering with Energy-Metabolism inPharmaceuticals (Basel, Switzerland) · 2020Review
- MmpL3 Inhibition: A New Approach to Treat Nontuberculous Mycobacterial Infections.International journal of molecular sciences · 2020Review
- Association between bacterial homoplastic variants and radiological pathology in tuberculosis.Thorax · 2020Article
- Fragment-Based Design ofJournal of medicinal chemistry · 2020Article
- Two Functional Fatty Acyl Coenzyme A Ligases Affect Free Fatty Acid Metabolism To Block Biosynthesis of an Antifungal Antibiotic in Lysobacter enzymogenes.Applied and environmental microbiology · 2020Article
- The quest for the holy grail: new antitubercular chemical entities, targets and strategies.Drug discovery today · 2020Review
- Cell Surface Biosynthesis and Remodeling Pathways in Mycobacteria Reveal New Drug Targets.Frontiers in cellular and infection microbiology · 2020Review
- The mycobacterial cell envelope - a moving target.Nature reviews. Microbiology · 2020Review
- Rational approaches, design strategies, structure activity relationship and mechanistic insights for therapeutic coumarin hybrids.Bioorganic & medicinal chemistry · 2019Review
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14 authors at 4 institutions in 1 country.
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Abstract
Infection with the bacterial pathogen Mycobacterium tuberculosis imposes an enormous burden on global public health. New antibiotics are urgently needed to combat the global tuberculosis pandemic; however, the development of new small molecules is hindered by a lack of validated drug targets. Here, we describe the identification of a 4,6-diaryl-5,7-dimethyl coumarin series that kills M. tuberculosis by inhibiting fatty acid degradation protein D32 (FadD32), an enzyme that is required for biosynthesis of cell-wall mycolic acids. These substituted coumarin inhibitors directly inhibit the acyl-acyl carrier protein synthetase activity of FadD32. They effectively block bacterial replication both in vitro and in animal models of tuberculosis, validating FadD32 as a target for antibiotic development that works in the same pathway as the established antibiotic isoniazid. Targeting new steps in well-validated biosynthetic pathways in antitubercular therapy is a powerful strategy that removes much of the usual uncertainty surrounding new targets and in vivo clinical efficacy, while circumventing existing resistance to established targets.
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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.