ArticlePloS one2013
Isozyme-specific ligands for O-acetylserine sulfhydrylase, a novel antibiotic target.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 59 citations in OpenAlex.
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- Betaine and I-LG may have a predictive value for ATB: A causal study in a large European population.PloS one · 2024Article
- Combatting antimicrobial resistance via the cysteine biosynthesis pathway in bacterial pathogens.Bioscience reports · 2022Review
- Novel eIF4A1 inhibitors with anti-tumor activity in lymphoma.Molecular medicine (Cambridge, Mass.) · 2022Article
- Screening of medicinal plants unraveled the leishmanicidal credibility ofJournal of parasitic diseases : official organ of the Indian Society for Parasitology · 2022Article
- Discovery of Substituted (2-Aminooxazol-4-yl)Isoxazole-3-carboxylic Acids as Inhibitors of Bacterial Serine Acetyltransferase in the Quest for Novel Potential Antibacterial Adjuvants.Pharmaceuticals (Basel, Switzerland) · 2021Article
- Inhibition of Nonessential Bacterial Targets: Discovery of a Novel SerineACS medicinal chemistry letters · 2020Article
- Discovery and Characterization of the Antimetabolite Action of Thioacetamide-Linked 1,2,3-Triazoles as Disruptors of Cysteine Biosynthesis in Gram-Negative Bacteria.ACS infectious diseases · 2020Article
- Refining the structure-activity relationships of 2-phenylcyclopropane carboxylic acids as inhibitors of O-acetylserine sulfhydrylase isoforms.Journal of enzyme inhibition and medicinal chemistry · 2019Article
- Combination of SAXS and Protein Painting Discloses the Three-Dimensional Organization of the Bacterial Cysteine Synthase Complex, a Potential Target for Enhancers of Antibiotic Action.International journal of molecular sciences · 2019Article
- Discovering New Casein Kinase 1d Inhibitors with an Innovative Molecular Dynamics Enabled Virtual Screening Workflow.ACS medicinal chemistry letters · 2019Article
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- First virtual screening and experimental validation of inhibitors targeting GES-5 carbapenemase.Journal of computer-aided molecular design · 2019Article
- Discovery of novel fragments inhibiting O-acetylserine sulphhydrylase by combining scaffold hopping and ligand-based drug design.Journal of enzyme inhibition and medicinal chemistry · 2018Article
- Computational and biological profile of boronic acids for the detection of bacterial serine- and metallo-β-lactamases.Scientific reports · 2017Article
- Genetic, metabolomic and transcriptomic analyses of the de novo L-cysteine biosynthetic pathway in the enteric protozoan parasite Entamoeba histolytica.Scientific reports · 2017Article
- Activation of an anti-bacterial toxin by the biosynthetic enzyme CysK: mechanism of binding, interaction specificity and competition with cysteine synthase.Scientific reports · 2017Article
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Authors and funding
12 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The last step of cysteine biosynthesis in bacteria and plants is catalyzed by O-acetylserine sulfhydrylase. In bacteria, two isozymes, O-acetylserine sulfhydrylase-A and O-acetylserine sulfhydrylase-B, have been identified that share similar binding sites, although the respective specific functions are still debated. O-acetylserine sulfhydrylase plays a key role in the adaptation of bacteria to the host environment, in the defense mechanisms to oxidative stress and in antibiotic resistance. Because mammals synthesize cysteine from methionine and lack O-acetylserine sulfhydrylase, the enzyme is a potential target for antimicrobials. With this aim, we first identified potential inhibitors of the two isozymes via a ligand- and structure-based in silico screening of a subset of the ZINC library using FLAP. The binding affinities of the most promising candidates were measured in vitro on purified O-acetylserine sulfhydrylase-A and O-acetylserine sulfhydrylase-B from Salmonella typhimurium by a direct method that exploits the change in the cofactor fluorescence. Two molecules were identified with dissociation constants of 3.7 and 33 µM for O-acetylserine sulfhydrylase-A and O-acetylserine sulfhydrylase-B, respectively. Because GRID analysis of the two isoenzymes indicates the presence of a few common pharmacophoric features, cross binding titrations were carried out. It was found that the best binder for O-acetylserine sulfhydrylase-B exhibits a dissociation constant of 29 µM for O-acetylserine sulfhydrylase-A, thus displaying a limited selectivity, whereas the best binder for O-acetylserine sulfhydrylase-A exhibits a dissociation constant of 50 µM for O-acetylserine sulfhydrylase-B and is thus 8-fold selective towards the former isozyme. Therefore, isoform-specific and isoform-independent ligands allow to either selectively target the isozyme that predominantly supports bacteria during infection and long-term survival or to completely block bacterial cysteine biosynthesis.
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