Drugging tRNA aminoacylation

Ho, Joanne M. L.; Bakkalbasi, Erol; Söll, Dieter; Miller, Christine

doi:10.1080/15476286.2018.1429879

Cited by 56 publications

(45 citation statements)

References 114 publications

(159 reference statements)

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“…Structural and biochemical properties of tRNA interactions with cognate aminoacyl‐tRNA synthetases, the “second code”, differ between bacterial pathogens and the human host. These differences have already been exploited with the bacterial isoleucyl‐tRNA synthetase inhibitor Mupirocin, and hold promise for other inhibitors . A “third code” is represented by the modified nucleotides of RNA, a distinct set of biomarkers, differing between bacteria and mammals that could be used to develop antibiotics .…”

Section: Discussionmentioning

confidence: 99%

“…These differences have already been exploited with the bacterial isoleucyl-tRNA synthetase inhibitorM upirocin, and hold promise for other inhibitors. [55] A" third code" is represented by the modified nucleotides of RNA,adistinct set of biomarkers, differing between bacteria and mammals that could be used to develop antibiotics. [56] Ribosomes have long been the target of clinically useful antibiotics.…”

Section: Discussionmentioning

confidence: 99%

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Discovery of Small‐Molecule Antibiotics against a Unique tRNA‐Mediated Regulation of Transcription in Gram‐Positive Bacteria

et al. 2019

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The emergence of multidrug‐resistant bacteria necessitates the identification of unique targets of intervention and compounds that inhibit their function. Gram‐positive bacteria use a well‐conserved tRNA‐responsive transcriptional regulatory element in mRNAs, known as the T‐box, to regulate the transcription of multiple operons that control amino acid metabolism. T‐box regulatory elements are found only in the 5′‐untranslated region (UTR) of mRNAs of Gram‐positive bacteria, not Gram‐negative bacteria or the human host. Using the structure of the 5′UTR sequence of the Bacillus subtilis tyrosyl‐tRNA synthetase mRNA T‐box as a model, in silico docking of 305 000 small compounds initially yielded 700 as potential binders that could inhibit the binding of the tRNA ligand. A single family of compounds inhibited the growth of Gram‐positive bacteria, but not Gram‐negative bacteria, including drug‐resistant clinical isolates at minimum inhibitory concentrations (MIC 16–64 μg mL−1). Resistance developed at an extremely low mutational frequency (1.21×10−10). At 4 μg mL−1, the parent compound PKZ18 significantly inhibited in vivo transcription of glycyl‐tRNA synthetase mRNA. PKZ18 also inhibited in vivo translation of the S. aureus threonyl‐tRNA synthetase protein. PKZ18 bound to the Specifier Loop in vitro (Kd≈24 μm). Its core chemistry necessary for antibacterial activity has been identified. These findings support the T‐box regulatory mechanism as a new target for antibiotic discovery that may impede the emergence of resistance.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Discovery of Small‐Molecule Antibiotics against a Unique tRNA‐Mediated Regulation of Transcription in Gram‐Positive Bacteria

et al. 2019

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“…Inhibition of protein synthesis by targeting tRNA aminoacylation has proven to be an effective strategy for anti-pathogenic drug development [128]. The catalytic domain of ARS has three distinct binding pockets responsible for recognition of amino acids, adenylate, and tRNA moieties [129].…”

Section: Representative Compounds Inhibiting Essential Functions Of Bmentioning

confidence: 99%

“…These enzymes are relatively easy to purify as recombinant proteins. Typical aminoacylation assays measuring the rate of AA-tRNA AA formation and kinetic assays to measure the rate of conversion of PPi into ATP using radioisotopes or specific organic compounds like malachite green are available for early characterization of ARS inhibitors [128,138].…”

Section: Developing Bacterial Ars Inhibitorsmentioning

confidence: 99%

Aminoacyl-tRNA synthetases, therapeutic targets for infectious diseases

Lee

Kim

2018

Biochemical Pharmacology

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Despite remarkable advances in medical science, infection-associated diseases remain among the leading causes of death worldwide. There is a great deal of interest and concern at the rate at which new pathogens are emerging and causing significant human health problems. Expanding our understanding of how cells regulate signaling networks to defend against invaders and retain cell homeostasis will reveal promising strategies against infection. It has taken scientists decades to appreciate that eukaryotic aminoacyl-tRNA synthetases (ARSs) play a role as global cell signaling mediators to regulate cell homeostasis, beyond their intrinsic function as protein synthesis enzymes. Recent discoveries revealed that ubiquitously expressed standby cytoplasmic ARSs sense and respond to danger signals and regulate immunity against infections, indicating their potential as therapeutic targets for infectious diseases. In this review, we discuss ARS-mediated anti-infectious signaling and the emerging role of ARSs in antimicrobial immunity. In contrast to their ability to defend against infection, host ARSs are inevitably co-opted by viruses for survival and propagation. We therefore provide a brief overview of the communication between viruses and the ARS system. Finally, we discuss encouraging new approaches to develop ARSs as therapeutics for infectious diseases.

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“…2 Each of the 20 amino acids has its own aminoacyl-tRNA synthetase (aaRS) which catalyses the attachment of the amino acid to its cognate tRNA. Despite the fact that all aaRSs share the same overall mechanism, it has long been recognised that there is clearly significant diversity between bacterial, mammalian and archaeal enzymes to allow for synthetic and natural product discrimination between pathogen and host enzymes [3][4][5] . In addition, in some situations, several different amino acids are able to bind to non-cognate aaRSs, requiring an in vivo editing function allowing for the possibility of exploiting this feature for future antimicrobial discovery 6 .…”

Section: Introductionmentioning

confidence: 99%

Structure-guided enhancement of selectivity of chemical probe inhibitors targeting bacterial seryl-tRNA synthetase

Cain¹,

Salimaraj²,

Punekar³

et al. 2019

Preprint

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Aminoacyl-tRNA synthetases are ubiquitous and essential enzymes for protein synthesis and also a variety of other metabolic processes, especially in bacterial species. Bacterial aminoacyl-tRNA synthetases represent attractive and validated targets for antimicrobial drug discovery if issues of prokaryotic versus eukaryotic selectivity and antibiotic resistance generation can be addressed. We have determined high resolution X-ray crystal structures of the Escherichia coli and Staphylococcus aureus seryl-tRNA synthetases in complex with aminoacyl adenylate analogues and applied a structure-based drug discovery approach to explore and identify a series of small molecule inhibitors that selectively inhibit bacterial seryl-tRNA synthetases with greater than two orders of magnitude compared to their human homologue, demonstrating a route to selective chemical inhibition of these bacterial targets.

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Drugging tRNA aminoacylation

Cited by 56 publications

References 114 publications

Discovery of Small‐Molecule Antibiotics against a Unique tRNA‐Mediated Regulation of Transcription in Gram‐Positive Bacteria

Discovery of Small‐Molecule Antibiotics against a Unique tRNA‐Mediated Regulation of Transcription in Gram‐Positive Bacteria

Aminoacyl-tRNA synthetases, therapeutic targets for infectious diseases

Structure-guided enhancement of selectivity of chemical probe inhibitors targeting bacterial seryl-tRNA synthetase

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