ArticleScientific reports2017
Inhibiting mycobacterial tryptophan synthase by targeting the inter-subunit interface.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 54 citations in OpenAlex.
- Defining thebioRxiv : the preprint server for biology · 2026Article
- Emerging therapeutic drug targets in amino acid and protein biosynthesis pathways against ESKAPE and non-ESKAPE pathogens: a comprehensive review.Archives of microbiology · 2026Review
- Genome-wide analysis of Brucella melitensis growth in spleen of infected mice allows rational selection of new vaccine candidates.PLoS pathogens · 2024Article
- 5-Fluoroindole Reduces the Bacterial Burden in a Murine Model ofACS omega · 2024Article
- Therapeutic developments for tuberculosis and nontuberculous mycobacterial lung disease.Nature reviews. Drug discovery · 2024Review
- Azetidines Kill Multidrug-ResistantJournal of medicinal chemistry · 2024Article
- Investigating the Roles of Active Site Residues inACS bio & med chem Au · 2023Article
- Review
- Hit Compounds and Associated Targets in IntracellularMolecules (Basel, Switzerland) · 2022Article
- Discovery of antimicrobial agent targeting tryptophan synthase.Protein science : a publication of the Protein Society · 2022Article
- Atomic-resolution chemical characterization of (2x)72-kDa tryptophan synthase via four- and five-dimensionalProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Indole-3-Glycerol Phosphate Synthase From Mycobacterium tuberculosis: A Potential New Drug Target.Chembiochem : a European journal of chemical biology · 2022Review
- An Outline of the Latest Crystallographic Studies on Inhibitor-Enzyme Complexes for the Design and Development of New Therapeutics against Tuberculosis.Molecules (Basel, Switzerland) · 2021Review
- Resistance of Mycobacterium tuberculosis to indole 4-carboxamides occurs through alterations in drug metabolism and tryptophan biosynthesis.Cell chemical biology · 2021Article
- Protocol: analytical methods for visualizing the indolic precursor network leading to auxin biosynthesis.Plant methods · 2021Article
- Microbiome-immune interactions in tuberculosis.PLoS pathogens · 2021Review
- Distinct conformational dynamics and allosteric networks in alpha tryptophan synthase during active catalysis.Protein science : a publication of the Protein Society · 2021Article
- Towards Photochromic Azobenzene-Based Inhibitors for Tryptophan Synthase.Chemistry (Weinheim an der Bergstrasse, Germany) · 2021Article
- Substitution of a Surface-Exposed Residue Involved in an Allosteric Network Enhances Tryptophan Synthase Function in Cells.Frontiers in molecular biosciences · 2021Article
- Anti-tubercular derivatives of rhein require activation by the monoglyceride lipase Rv0183.Cell surface (Amsterdam, Netherlands) · 2020Article
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 2 countries.
Funding
Abstract
Drug discovery efforts against the pathogen Mycobacterium tuberculosis (Mtb) have been advanced through phenotypic screens of extensive compound libraries. Such a screen revealed sulfolane 1 and indoline-5-sulfonamides 2 and 3 as potent inhibitors of mycobacterial growth. Optimization in the sulfolane series led to compound 4, which has proven activity in an in vivo murine model of Mtb infection. Here we identify the target and mode of inhibition of these compounds based on whole genome sequencing of spontaneous resistant mutants, which identified mutations locating to the essential α- and β-subunits of tryptophan synthase. Over-expression studies confirmed tryptophan synthase as the biological target. Biochemical techniques probed the mechanism of inhibition, revealing the mutant enzyme complex incurs a fitness cost but does not prevent inhibitor binding. Mapping of the resistance conferring mutations onto a low-resolution crystal structure of Mtb tryptophan synthase showed they locate to the interface between the α- and β-subunits. The discovery of anti-tubercular agents inhibiting tryptophan synthase highlights the therapeutic potential of this enzyme and draws attention to the prospect of other amino acid biosynthetic pathways as future Mtb drug 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.