ArticleAntimicrobial agents and chemotherapy2005
Mode of action and biochemical characterization of REP8839, a novel inhibitor of methionyl-tRNA synthetase.
Article in Antimicrobial agents and chemotherapy, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 54 citations in OpenAlex.
- Discovery of a triple-site inhibitor targeting bacterial methionyl-tRNA synthetase through combined drug repurposing screening and generative AI-assisted optimization.Nucleic acids research · 2026Article
- Repurposing antibacterial drugs identifies ridinilazole and CRS3123 as promising candidates against vancomycin-resistant enterococci.Scientific reports · 2025Article
- Fighting Antimicrobial Resistance: Innovative Drugs in Antibacterial Research.Angewandte Chemie (International ed. in English) · 2025Review
- A novel methionyl-tRNA synthetase inhibitor targeting gram-positive bacterial pathogens.Antimicrobial agents and chemotherapy · 2024Article
- Potential Piperolactam A Isolated From Piper betle as Natural Inhibitors of Brucella Species Aminoacyl-tRNA Synthetase for Livestock Infections: In Silico Approach.Veterinary medicine and science · 2024Article
- Tunicamycins from Marine-DerivedMarine drugs · 2024Article
- ExploringPharmaceuticals (Basel, Switzerland) · 2023Article
- Spontaneous Selection ofAntimicrobial agents and chemotherapy · 2021Article
- Aminoacyl-tRNA Synthetases as Valuable Targets for Antimicrobial Drug Discovery.International journal of molecular sciences · 2021Review
- Discovery of an Allosteric Binding Site in Kinetoplastid Methionyl-tRNA Synthetase.ACS infectious diseases · 2020Article
- Development of Methionyl-tRNA Synthetase Inhibitors as Antibiotics for Gram-Positive Bacterial Infections.Antimicrobial agents and chemotherapy · 2017Article
- Safety, Tolerability, Systemic Exposure, and Metabolism of CRS3123, a Methionyl-tRNA Synthetase Inhibitor Developed for Treatment of Clostridium difficile, in a Phase 1 Study.Antimicrobial agents and chemotherapy · 2017Article
- Ligand co-crystallization of aminoacyl-tRNA synthetases from infectious disease organisms.Scientific reports · 2017Article
- Targeting Multiple Aminoacyl-tRNA Synthetases Overcomes the Resistance Liabilities Associated with Antibacterial Inhibitors Acting on a Single Such Enzyme.Antimicrobial agents and chemotherapy · 2016Article
- Discovery and Analysis of Natural-Product Compounds Inhibiting Protein Synthesis in Pseudomonas aeruginosa.Antimicrobial agents and chemotherapy · 2016Article
- Inhibition of protein synthesis and malaria parasite development by drug targeting of methionyl-tRNA synthetases.Antimicrobial agents and chemotherapy · 2015Article
- Methionine biosynthesis in Staphylococcus aureus is tightly controlled by a hierarchical network involving an initiator tRNA-specific T-box riboswitch.PLoS pathogens · 2013Article
- The antibiotic Furvina® targets the P-site of 30S ribosomal subunits and inhibits translation initiation displaying start codon bias.Nucleic acids research · 2012Article
- Expedient synthesis of α-substituted fluoroethenes.Organic & biomolecular chemistry · 2012Article
- Development of 4H-pyridopyrimidines: a class of selective bacterial protein synthesis inhibitors.Organic and medicinal chemistry letters · 2012Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aminoacyl-tRNA synthetases have attracted interest as essential and novel targets involved in bacterial protein synthesis. REP8839 is a potent inhibitor of MetS, the methionyl-tRNA synthetase in Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), and in Streptococcus pyogenes. The biochemical activity of REP8839 was shown by specific inhibition of purified S. aureus MetS (50% inhibitory concentration, <1.9 nM). Target specificity was confirmed by overexpression of the metS gene in S. aureus, resulting in an eightfold increase in the MIC for REP8839. Macromolecular synthesis assays in the presence of REP8839 demonstrated a dose-dependent inhibition of protein synthesis and RNA synthesis in S. pneumoniae R6, but only protein synthesis was affected in an isogenic rel mutant deficient in the stringent response. Strains with reduced susceptibility to REP8839 were generated by selection of strains with spontaneous mutations and through serial passages. Point mutations within the metS gene were mapped, leading to a total of 23 different amino acid substitutions within MetS that were located around the modeled active site. The most frequent MetS mutations were I57N, leading to a shift in the MIC from 0.06 microg/ml to 4 microg/ml, and G54S, resulting in a MIC of 32 microg/ml that was associated with a reduced growth rate. The mutation prevention concentration was 32 microg/ml in four S. aureus strains (methicillin-sensitive S. aureus and MRSA), which is well below the drug concentration of 2% (20,000 microg/ml) in a topical formulation. In conclusion, we demonstrate by biochemical, physiologic, and genetic mode-of-action studies that REP8839 exerts its antibacterial activity through specific inhibition of MetS, a novel target.
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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.