ArticleThe Journal of biological chemistry2014
Inactivation of the Mycobacterium tuberculosis antigen 85 complex by covalent, allosteric inhibitors.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed.
- Key Proteins and Enzymatic Mechanisms Underlying Drug Resistance in Mycobacterium tuberculosis.Advances in experimental medicine and biology · 2026Review
- Antibacterial Activity of Ebselen.International journal of molecular sciences · 2023Review
- Mycobacterial Adhesion: From Hydrophobic to Receptor-Ligand Interactions.Microorganisms · 2022Review
- Recent Progress in the Development of Novel Mycobacterium Cell Wall Inhibitor to Combat Drug-Resistant Tuberculosis.Microbiology insights · 2022Review
- Total Synthesis of Tetrahydrolipstatin, Its Derivatives, and Evaluation of Their Ability to Potentiate Multiple Antibiotic Classes againstACS infectious diseases · 2021Article
- Antibiotics and resistance: the two-sided coin of the mycobacterial cell wall.Cell surface (Amsterdam, Netherlands) · 2020Review
- Article
- Structure, Mechanism, and Inhibition ofAntimicrobial agents and chemotherapy · 2019Article
- Mycolyltransferase fromThe Journal of biological chemistry · 2018Article
- Cyclipostins and cyclophostin analogs inhibit the antigen 85C fromThe Journal of biological chemistry · 2018Article
- An Antibacterial β-Lactone Kills Mycobacterium tuberculosis by Disrupting Mycolic Acid Biosynthesis.Angewandte Chemie (International ed. in English) · 2018Article
- Exploring Covalent Allosteric Inhibition of Antigen 85C from Mycobacterium tuberculosis by Ebselen Derivatives.ACS infectious diseases · 2017Article
- Thermal and Photoinduced Copper-Promoted C-Se Bond Formation: Synthesis of 2-Alkyl-1,2-benzisoselenazol-3(2H)-ones and Evaluation against Mycobacterium tuberculosis.The Journal of organic chemistry · 2017Article
- Visualization of mycobacterial membrane dynamics in live cells.Journal of the American Chemical Society · 2017Article
- Development of ebsulfur analogues as potent antibacterials against methicillin-resistant Staphylococcus aureus.Bioorganic & medicinal chemistry · 2016Article
- Small-Molecule Probes Reveal Esterases with Persistent Activity in Dormant and Reactivating Mycobacterium tuberculosis.ACS infectious diseases · 2016Article
- Enabling systematic interrogation of protein-protein interactions in live cells with a versatile ultra-high-throughput biosensor platform.Journal of molecular cell biology · 2016Article
- Mycobacterium tuberculosis Thioredoxin Reductase Is Essential for Thiol Redox Homeostasis but Plays a Minor Role in Antioxidant Defense.PLoS pathogens · 2016Article
- Ebselen, a Small-Molecule Capsid Inhibitor of HIV-1 Replication.Antimicrobial agents and chemotherapy · 2016Article
- Functional insights from a comparative study on the dynamics of Antigen85 proteins and MPT51 from Mycobacterium tuberculosis.Journal of molecular modeling · 2015Article
Corrections and comments
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Authors and funding
3 authors.
Funding
Abstract
The rise of multidrug-resistant and totally drug-resistant tuberculosis and the association with an increasing number of HIV-positive patients developing tuberculosis emphasize the necessity to find new antitubercular targets and drugs. The antigen 85 (Ag85) complex from Mycobacterium tuberculosis plays important roles in the biosynthesis of major components of the mycobacterial cell envelope. For this reason, Ag85 has emerged as an attractive drug target. Recently, ebselen was identified as an effective inhibitor of the Ag85 complex through covalent modification of a cysteine residue proximal to the Ag85 active site and is therefore a covalent, allosteric inhibitor. To expand the understanding of this process, we have solved the x-ray crystal structures of Ag85C covalently modified with ebselen and other thiol-reactive compounds, p-chloromercuribenzoic acid and iodoacetamide, as well as the structure of a cysteine to glycine mutant. All four structures confirm that chemical modification or mutation at this particular cysteine residue leads to the disruption of the active site hydrogen-bonded network essential for Ag85 catalysis. We also describe x-ray crystal structures of Ag85C single mutants within the catalytic triad and show that a mutation of any one of these three residues promotes the same conformational change observed in the cysteine-modified forms. These results provide evidence for active site dynamics that may afford new strategies for the development of selective and potent Ag85 inhibitors.
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Registered trials
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