ArticlePloS one2014
Biochemical and structural characterization of mycobacterial aspartyl-tRNA synthetase AspS, a promising TB drug target.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed.
- Article
- Hit Compounds and Associated Targets in IntracellularMolecules (Basel, Switzerland) · 2022Article
- Antitubercular, Cytotoxicity, and Computational Target Validation of Dihydroquinazolinone Derivatives.Antibiotics (Basel, Switzerland) · 2022Article
- Article
- An anti-tuberculosis compound screen using a zebrafish infection model identifies an aspartyl-tRNA synthetase inhibitor.Disease models & mechanisms · 2021Article
- Clinically Relevant Mutations of Mycobacterial GatCAB Inform Regulation of Translational Fidelity.mBio · 2021Article
- Anti-tubercular derivatives of rhein require activation by the monoglyceride lipase Rv0183.Cell surface (Amsterdam, Netherlands) · 2020Article
- Mycobacterial drug discovery.RSC medicinal chemistry · 2020Review
- Development of a novel secondary phenotypic screen to identify hits within the mycobacterial protein synthesis pipeline.FASEB bioAdvances · 2020Article
- Comparative genomics of Mycobacterium mucogenicum and Mycobacterium neoaurum clade members emphasizing tRNA and non-coding RNA.BMC evolutionary biology · 2019Article
- Development of a whole-cell high-throughput phenotypic screen to identify inhibitors of mycobacterial amino acid biosynthesis.FASEB bioAdvances · 2019Article
- Utilisation of the Prestwick Chemical Library to identify drugs that inhibit the growth of mycobacteria.PloS one · 2019Article
- Identification and characterization of aspartyl-tRNA synthetase inhibitors against Mycobacterium tuberculosis by an integrated whole-cell target-based approach.Scientific reports · 2018Article
- Mycobacterial cell wall biosynthesis: a multifaceted antibiotic target.Parasitology · 2018Review
- A Metabolomics Pilot Study on Desmoid Tumors and Novel Drug Candidates.Scientific reports · 2018Article
- Linking common non-coding RNAs of human lung cancer and M. tuberculosis.Bioinformation · 2018Article
- Inhibiting mycobacterial tryptophan synthase by targeting the inter-subunit interface.Scientific reports · 2017Article
- Identification of KasA as the cellular target of an anti-tubercular scaffold.Nature communications · 2016Article
- Aminoacyl-tRNA Synthetases in the Bacterial World.EcoSal Plus · 2016Review
- THPP target assignment reveals EchA6 as an essential fatty acid shuttle in mycobacteria.Nature microbiology · 2016Article
Corrections and comments
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Authors and funding
16 authors.
Funding
Abstract
The human pathogen Mycobacterium tuberculosis is the causative agent of pulmonary tuberculosis (TB), a disease with high worldwide mortality rates. Current treatment programs are under significant threat from multi-drug and extensively-drug resistant strains of M. tuberculosis, and it is essential to identify new inhibitors and their targets. We generated spontaneous resistant mutants in Mycobacterium bovis BCG in the presence of 10× the minimum inhibitory concentration (MIC) of compound 1, a previously identified potent inhibitor of mycobacterial growth in culture. Whole genome sequencing of two resistant mutants revealed in one case a single nucleotide polymorphism in the gene aspS at (535)GAC>(535)AAC (D179N), while in the second mutant a single nucleotide polymorphism was identified upstream of the aspS promoter region. We probed whole cell target engagement by overexpressing either M. bovis BCG aspS or Mycobacterium smegmatis aspS, which resulted in a ten-fold and greater than ten-fold increase, respectively, of the MIC against compound 1. To analyse the impact of inhibitor 1 on M. tuberculosis AspS (Mt-AspS) activity we over-expressed, purified and characterised the kinetics of this enzyme using a robust tRNA-independent assay adapted to a high-throughput screening format. Finally, to aid hit-to-lead optimization, the crystal structure of apo M. smegmatis AspS was determined to a resolution of 2.4 Å.
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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.