ArticleNature chemical biology2017
A small-molecule allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase.
Article in Nature chemical biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers.
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Who cites it
67 citing papers in PubMed, 117 citations in OpenAlex.
- Isotopic tracing inVirulence · 2026Article
- Induced alanine auxotrophy as a therapeutic strategy against Mycobacterium tuberculosis.Research square · 2026Article
- Induced alanine auxotrophy as a therapeutic strategy againstbioRxiv : the preprint server for biology · 2026Article
- The Pyridoxal-5'-Phosphate-Dependent Enzymes ofACS infectious diseases · 2026Review
- Emerging therapeutic drug targets in amino acid and protein biosynthesis pathways against ESKAPE and non-ESKAPE pathogens: a comprehensive review.Archives of microbiology · 2026Review
- Reference-based chemical-genetic interaction profiling to elucidate small molecule mechanism of action in Mycobacterium tuberculosis.Nature communications · 2025Article
- Cryo-EM structures of Mycobacterium tuberculosis imidazole glycerol phosphate dehydratase in the apo state and in the presence of small molecules.Acta crystallographica. Section F, Structural biology communications · 2025Article
- 3-Hydroxykynurenine targets kainate receptors to promote defense against infection.Nature chemical biology · 2024Article
- 5-Fluoroindole Reduces the Bacterial Burden in a Murine Model ofACS omega · 2024Article
- Tryptophan catabolism via the kynurenine pathway regulates infection and inflammation: from mechanisms to biomarkers and therapies.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2024Review
- Transposon sequencing reveals metabolic pathways essential for Mycobacterium tuberculosis infection.PLoS pathogens · 2024Article
- Fungi Tryptophan Synthases: What Is the Role of the Linker Connecting the α and β Structural Domains inMolecules (Basel, Switzerland) · 2024Article
- Review
- DXP Synthase Function in a Bacterial Metabolic Adaptation and Implications for Antibacterial Strategies.Antibiotics (Basel, Switzerland) · 2023Article
- Distinct ecological fitness factors coordinated by a conservedProceedings of the National Academy of Sciences of the United States of America · 2023Article
- An Evolutionary Conservation and Druggability Analysis of Enzymes Belonging to the Bacterial Shikimate Pathway.Antibiotics (Basel, Switzerland) · 2022Article
- Computational Analysis on the Allostery of Tryptophan Synthase: Relationship between α/β-Ligand Binding and Distal Domain Closure.The journal of physical chemistry. B · 2022Article
- Discovery of antimicrobial agent targeting tryptophan synthase.Protein science : a publication of the Protein Society · 2022Article
- Indole-3-Glycerol Phosphate Synthase From Mycobacterium tuberculosis: A Potential New Drug Target.Chembiochem : a European journal of chemical biology · 2022Review
- Understanding the contribution of metabolism toFrontiers in cellular and infection microbiology · 2022Review
7 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 4 institutions in 1 country.
Funding
Abstract
New antibiotics with novel targets are greatly needed. Bacteria have numerous essential functions, but only a small fraction of such processes-primarily those involved in macromolecular synthesis-are inhibited by current drugs. Targeting metabolic enzymes has been the focus of recent interest, but effective inhibitors have been difficult to identify. We describe a synthetic azetidine derivative, BRD4592, that kills Mycobacterium tuberculosis (Mtb) through allosteric inhibition of tryptophan synthase (TrpAB), a previously untargeted, highly allosterically regulated enzyme. BRD4592 binds at the TrpAB α-β-subunit interface and affects multiple steps in the enzyme's overall reaction, resulting in inhibition not easily overcome by changes in metabolic environment. We show that TrpAB is required for the survival of Mtb and Mycobacterium marinum in vivo and that this requirement may be independent of an adaptive immune response. This work highlights the effectiveness of allosteric inhibition for targeting proteins that are naturally highly dynamic and that are essential in vivo, despite their apparent dispensability under in vitro conditions, and suggests a framework for the discovery of a next generation of allosteric inhibitors.
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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.