The identification of quality antibacterial drug discovery targets: a case study with aminoacyl-tRNA synthetases

Gallant, Paul; Finn, John M.; Keith, Dennis D.; Wendler, Philip A.

doi:10.1517/14728222.4.1.1

Cited by 27 publications

(12 citation statements)

References 20 publications

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“…Aminoacyl-RSs (aa-RSs) attracted interest as potential novel targets in bacterial protein synthesis, because they are indispensable for the highly specific translation of the mRNA template into protein via specific transfer RNAs (tRNAs) as adapter molecules (16,36). In the present study we focused on phenylalanyl (Phe)-tRNA synthetase (Phe-RS), which is responsible for coupling the amino acid Phe to the corresponding Phe-specific tRNA (tRNA Phe ) (4).…”

mentioning

confidence: 99%

“…Subsequent investigators question this interpretation, nevertheless, as the concentration of ochratoxin in Bacillus subtilis appears to be too low to significantly compete with phenylalanine for the binding site of Phe-RS (33). For other aa-RS enzymes several inhibitors have been patented and reported in the literature over the years (6,16,40), but none of them has been developed as an antibacterial agent so far.…”

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confidence: 99%

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New Class of Bacterial Phenylalanyl-tRNA Synthetase Inhibitors with High Potency and Broad-Spectrum Activity

Beyer¹,

Kroll²,

Endermann³

et al. 2004

Antimicrob Agents Chemother

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Phenylalanyl (Phe)-tRNA synthetase (Phe-RS) is an essential enzyme which catalyzes the transfer of phenylalanine to the Phe-specific transfer RNA (tRNA Phe ), a key step in protein biosynthesis. Phenyl-thiazolylurea-sulfonamides were identified as a novel class of potent inhibitors of bacterial Phe-RS by highthroughput screening and chemical variation of the screening hit. The compounds inhibit Phe-RS of Escherichia coli, Haemophilus influenzae, Streptococcus pneumoniae, and Staphylococcus aureus, with 50% inhibitory concentrations in the nanomolar range. Enzyme kinetic measurements demonstrated that the compounds bind competitively with respect to the natural substrate Phe. All derivatives are highly selective for the bacterial Phe-RS versus the corresponding mammalian cytoplasmic and human mitochondrial enzymes. Phenyl-thiazolylurea-sulfonamides displayed good in vitro activity against Staphylococcus, Streptococcus, Haemophilus, and Moraxella strains, reaching MICs below 1 g/ml. The antibacterial activity was partly antagonized by increasing concentrations of Phe in the culture broth in accordance with the competitive binding mode. Further evidence that inhibition of tRNA Phe charging is the antibacterial principle of this compound class was obtained by proteome analysis of Bacillus subtilis. Here, the phenyl-thiazolylurea-sulfonamides induced a protein pattern indicative of the stringent response. In addition, an E. coli strain carrying a relA mutation and defective in stringent response was more susceptible than its isogenic relA ؉ parent strain. In vivo efficacy was investigated in a murine S. aureus sepsis model and a S. pneumoniae sepsis model in rats. Treatment with the phenylthiazolylurea-sulfonamides reduced the bacterial titer in various organs by up to 3 log units, supporting the potential value of Phe-RS as a target in antibacterial therapy.

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confidence: 99%

mentioning

confidence: 99%

New Class of Bacterial Phenylalanyl-tRNA Synthetase Inhibitors with High Potency and Broad-Spectrum Activity

Beyer¹,

Kroll²,

Endermann³

et al. 2004

Antimicrob Agents Chemother

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“…(iii) The full complement of 20 synthetases is found in most bacterial pathogens and may represent 20 independent antibacterial targets (49,72). (iv) These enzymes are soluble, stable, and easy to purify in large quantities from recombinant expression systems and can be assayed by one or more conventional methods which are amenable to highthroughput screening (37,61). (v) X-ray crystal structures for most of the synthetases have been solved and provide a platform for rational drug design (49,71).…”

Section: Aminoacyl-trna Synthetases As Novel Antibacterial Targetsmentioning

confidence: 99%

“…Dramatic progress in automated high-throughput screening technology is currently acting as an important approach for discovering low-molecular-weight molecules which perturb the function of AaRS enzymes (37). Chemical optimization of these hits has led to the generation of multiple series of pharmacophores which inhibit bacterial AaRS enzymes and which represent clinical candidates.…”

Section: Synthetic and Semisynthetic Trna Synthetase Inhibitorsmentioning

confidence: 99%

“…In recent years, reports of compounds (both natural and synthetic) which inhibit AaRS have increased. While many of these new inhibitors also affect the counterpart human enzymes, there has been some success in identifying molecules that are specific for bacterial AaRS enzymes and that also exhibit antibacterial activities against several species in experimental infections (37,54,71,75). However, mupirocin is currently the only clinically available AaRS inhibitor and therefore acts as the paradigm for the prospective clinical development and deployment of future AaRS inhibitors.…”

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Prospects for Aminoacyl-tRNA Synthetase Inhibitors as New Antimicrobial Agents

Hurdle

O’Neill

Chopra

2005

Antimicrob Agents Chemother

191

172

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Synthesis and Antibacterial Activity of New Diaryldiamines

Samrin¹,

Sharma

Khan

et al. 2012

Journal of Heterocyclic Chem

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View this article online at wileyonlinelibrary.com.Several new quinolines and quinazolines (4, 10, 13) have been synthesized from cheap and readily available chemicals through a series of simple chemical transformations. Most of the synthesized compounds have been evaluated for antibacterial activity against Gram positive and Gram negative strains. Some of the synthesized compounds displayed interesting activity but not very promising for further development.

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The identification of quality antibacterial drug discovery targets: a case study with aminoacyl-tRNA synthetases

Cited by 27 publications

References 20 publications

New Class of Bacterial Phenylalanyl-tRNA Synthetase Inhibitors with High Potency and Broad-Spectrum Activity

New Class of Bacterial Phenylalanyl-tRNA Synthetase Inhibitors with High Potency and Broad-Spectrum Activity

Prospects for Aminoacyl-tRNA Synthetase Inhibitors as New Antimicrobial Agents

Synthesis and Antibacterial Activity of New Diaryldiamines

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