Aminoacyl-tRNA Synthetases as Valuable Targets for Antimicrobial Drug Discovery

Pang, Liuqing; Weeks, S.D.

doi:10.3390/ijms22041750

Cited by 51 publications

(50 citation statements)

References 178 publications

(283 reference statements)

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“…[ 69 ]. While not a current antimicrobial target, there has been an effort to link mutations in tRNA-ligase to AMR in M. bovis [ 26 ], which could possibly identify targets for using aminoacyl-tRNA synthetase inhibitors as antimicrobials [ 55 , 70 ]. Ledger et al listed 22 tRNA ligases, 13 of which we identified as containing NVs to AMR [ 26 ].…”

Section: Resultsmentioning

confidence: 99%

Genome-Wide Association Study of Nucleotide Variants Associated with Resistance to Nine Antimicrobials in Mycoplasma bovis

et al. 2022

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Antimicrobial resistance (AMR) studies of Mycoplasma bovis have generally focused on specific loci versus using a genome-wide association study (GWAS) approach. A GWAS approach, using two different models, was applied to 194 Mycoplasma bovis genomes. Both a fixed effects linear model (FEM) and a linear mixed model (LMM) identified associations between nucleotide variants (NVs) and antimicrobial susceptibility testing (AST) phenotypes. The AMR phenotypes represented fluoroquinolones, tetracyclines, phenicols, and macrolides. Both models identified known and novel NVs associated (Bonferroni adjusted p < 0.05) with AMR. Fluoroquinolone resistance was associated with multiple NVs, including previously identified mutations in gyrA and parC. NVs in the 30S ribosomal protein 16S were associated with tetracycline resistance, whereas NVs in 5S rRNA, 23S rRNA, and 50S ribosomal proteins were associated with phenicol and macrolide resistance. For all antimicrobial classes, resistance was associated with NVs in genes coding for ABC transporters and other membrane proteins, tRNA-ligases, peptidases, and transposases, suggesting a NV-based multifactorial model of AMR in M. bovis. This study was the largest collection of North American M. bovis isolates used with a GWAS for the sole purpose of identifying novel and non-antimicrobial-target NVs associated with AMR.

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Section: Resultsmentioning

confidence: 99%

Genome-Wide Association Study of Nucleotide Variants Associated with Resistance to Nine Antimicrobials in Mycoplasma bovis

et al. 2022

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“…Aminoacyl-tRNA synthetases (aaRSs), catalysing the formation of aminoacyl-tRNA, have been explored as targets for the development of antimicrobials [9,[32][33][34][35]. However, HcProRS, located at the C-terminal region of a dual function EPRS, is likewise recognized as a promising target for anti-cancer [12][13][14], anti-fibrosis [11,36] and anti-autoimmune response [37] drug development.…”

Section: Discussionmentioning

confidence: 99%

Towards Novel 3-Aminopyrazinamide-Based Prolyl-tRNA Synthetase Inhibitors: In Silico Modelling, Thermal Shift Assay and Structural Studies

Pang

Weeks

Juhás

et al. 2021

IJMS

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Human cytosolic prolyl-tRNA synthetase (HcProRS) catalyses the formation of the prolyl-tRNAPro, playing an important role in protein synthesis. Inhibition of HcProRS activity has been shown to have potential benefits in the treatment of fibrosis, autoimmune diseases and cancer. Recently, potent pyrazinamide-based inhibitors were identified by a high-throughput screening (HTS) method, but no further elaboration was reported. The pyrazinamide core is a bioactive fragment found in numerous clinically validated drugs and has been subjected to various modifications. Therefore, we applied a virtual screening protocol to our in-house library of pyrazinamide-containing small molecules, searching for potential novel HcProRS inhibitors. We identified a series of 3-benzylaminopyrazine-2-carboxamide derivatives as positive hits. Five of them were confirmed by a thermal shift assay (TSA) with the best compounds 3b and 3c showing EC50 values of 3.77 and 7.34 µM, respectively, in the presence of 1 mM of proline (Pro) and 3.45 µM enzyme concentration. Co-crystal structures of HcProRS in complex with these compounds and Pro confirmed the initial docking studies and show how the Pro facilitates binding of the ligands that compete with ATP substrate. Modelling 3b into other human class II aminoacyl-tRNA synthetases (aaRSs) indicated that the subtle differences in the ATP binding site of these enzymes likely contribute to its potential selective binding of HcProRS. Taken together, this study successfully identified novel HcProRS binders from our anti-tuberculosis in-house compound library, displaying opportunities for repurposing old drug candidates for new applications such as therapeutics in HcProRS-related diseases.

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“…All organisms, including archaea, bacteria, and eukaryotic cells, have ARSs. ARSs are protein synthesis housekeeping enzymes that play an important role in the attachment of tRNAs to their cognate amino acids. , ARSs have been shown in studies to have multiple functions in addition to their catalytic roles. ARSs are thought to be involved in a variety of cellular processes and to contribute to pathophysiological processes. , The nutrient signaling pathways control various signaling cascades that govern cellular energy metabolism as well as cell growth, proliferation, and survival .…”

Section: Discussionmentioning

confidence: 99%

Tavaborole-Induced Inhibition of the Aminoacyl-tRNA Biosynthesis Pathway against Botrytis cinerea Contributes to Disease Control and Fruit Quality Preservation

Zhao

et al. 2022

J. Agric. Food Chem.

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The inhibitory effect of tavaborole on the invasion of Botrytis cinerea in grapes and tomatoes, as well as the potential mechanism involved, was discovered in this study. Our findings showed that tavaborole inhibited Botrytis cinerea spore germination and mycelial expansion in vitro and that the control efficiency in vivo on fruit decay was dose-dependent, which was effective in reducing disease severity and maintaining the organoleptic quality of the fruit, such as reducing weight loss and retaining fruit hardness and titratable acid contents during storage. Furthermore, the precise mechanism of action was investigated further. Propidium iodide staining revealed that Botrytis cinerea treated with tavaborole lost membrane integrity. For further validation, cytoplasmic malondialdehyde accumulation and leakage of cytoplasmic constituents were determined. Notably, the inhibitory effect was also dependent on inhibiting the activities of aminoacyl-tRNA synthetases involved in the aminoacyl-tRNA biosynthesis pathway in Botrytis cinerea. The above findings concluded that tavaborole was effective against Botrytis cinerea infection in postharvest fruit, and a related mechanism was also discussed, which may provide references for the drug repurposing of tavaborole as a postharvest fungicide.

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Aminoacyl-tRNA Synthetases as Valuable Targets for Antimicrobial Drug Discovery

Cited by 51 publications

References 178 publications

Genome-Wide Association Study of Nucleotide Variants Associated with Resistance to Nine Antimicrobials in Mycoplasma bovis

Genome-Wide Association Study of Nucleotide Variants Associated with Resistance to Nine Antimicrobials in Mycoplasma bovis

Towards Novel 3-Aminopyrazinamide-Based Prolyl-tRNA Synthetase Inhibitors: In Silico Modelling, Thermal Shift Assay and Structural Studies

Tavaborole-Induced Inhibition of the Aminoacyl-tRNA Biosynthesis Pathway against Botrytis cinerea Contributes to Disease Control and Fruit Quality Preservation

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