ArticleThe Journal of biological chemistry2014
The role of a novel auxiliary pocket in bacterial phenylalanyl-tRNA synthetase druggability.
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 19 papers.
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Who cites it
19 citing papers in PubMed, 29 citations in OpenAlex.
- NovelPathogens (Basel, Switzerland) · 2026Article
- Indel-driven evolution of the canavanine tRNA-editing deacetylase enzyme CtdA.Journal of structural biology: X · 2025Article
- Different chemical scaffolds bind to L-phe site in Mycobacterium tuberculosis Phe-tRNA synthetase.European journal of medicinal chemistry · 2025Article
- Specific glycine-dependent enzyme motion determines the potency of conformation selective inhibitors of threonyl-tRNA synthetase.Communications biology · 2024Article
- DataDTA: a multi-feature and dual-interaction aggregation framework for drug-target binding affinity prediction.Bioinformatics (Oxford, England) · 2023Article
- Novel Thiadiazole-Based Molecules as Promising Inhibitors of Black Fungi and Pathogenic Bacteria: In Vitro Antimicrobial Evaluation and Molecular Docking Studies.Molecules (Basel, Switzerland) · 2022Article
- Phenylalanyl tRNA synthetase (PheRS) substrate mimics: design, synthesis, molecular dynamics and antimicrobial evaluation.RSC advances · 2022Article
- Oxidation alters the architecture of the phenylalanyl-tRNA synthetase editing domain to confer hyperaccuracy.Nucleic acids research · 2021Article
- Design, computational studies, synthesis and in vitro antimicrobial evaluation of benzimidazole based thio-oxadiazole and thio-thiadiazole analogues.BMC chemistry · 2021Article
- Mycobacterium tuberculosis Phe-tRNA synthetase: structural insights into tRNA recognition and aminoacylation.Nucleic acids research · 2021Article
- Aminoacyl-tRNA synthetases.RNA (New York, N.Y.) · 2020Review
- Drugging tRNA aminoacylation.RNA biology · 2018Review
- Protein Translation Enzyme lysyl-tRNA Synthetase Presents a New Target for Drug Development against Causative Agents of Loiasis and Schistosomiasis.PLoS neglected tropical diseases · 2016Article
- Discovery and Analysis of Natural-Product Compounds Inhibiting Protein Synthesis in Pseudomonas aeruginosa.Antimicrobial agents and chemotherapy · 2016Article
- Aminoacyl-tRNA Synthetases in the Bacterial World.EcoSal Plus · 2016Review
- Evolutionary Limitation and Opportunities for Developing tRNA Synthetase Inhibitors with 5-Binding-Mode Classification.Life (Basel, Switzerland) · 2015Review
- A binding hotspot in Trypanosoma cruzi histidyl-tRNA synthetase revealed by fragment-based crystallographic cocktail screens.Acta crystallographica. Section D, Biological crystallography · 2015Article
- High Throughput Screen Identifies Natural Product Inhibitor of Phenylalanyl-tRNA Synthetase from Pseudomonas aeruginosa and Streptococcus pneumoniae.Current drug discovery technologies · 2014Article
- Rediscovery of PF-3845 as a new chemical scaffold inhibiting phenylalanyl-tRNA synthetase in Mycobacterium tuberculosis.The Journal of biological chemistryArticle
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The antimicrobial activity of phenyl-thiazolylurea-sulfonamides against Staphylococcus aureus PheRS are dependent upon phenylalanine levels in the extracellular fluids. Inhibitor efficacy in animal models of infection is substantially diminished by dietary phenylalanine intake, thereby reducing the perceived clinical utility of this inhibitor class. The search for novel antibacterial compounds against Gram-negative pathogens led to a re-evaluation of this phenomenon, which is shown here to be unique to S. aureus. Inhibition of macromolecular syntheses and characterization of novel resistance mutations in Escherichia coli demonstrate that antimicrobial activity of phenyl-thiazolylurea-sulfonamides is mediated by PheRS inhibition, validating this enzyme as a viable drug discovery target for Gram-negative pathogens. A search for novel inhibitors of PheRS yielded three novel chemical starting points. NMR studies were used to confirm direct target engagement for phenylalanine-competitive hits. The crystallographic structure of Pseudomonas aeruginosa PheRS defined the binding modes of these hits and revealed an auxiliary hydrophobic pocket that is positioned adjacent to the phenylalanine binding site. Three viable inhibitor-resistant mutants were mapped to this pocket, suggesting that this region is a potential liability for drug discovery.
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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.