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Review

Aminoacyl-tRNA Synthetases as Valuable Targets for Antimicrobial Drug Discovery

1
KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Herestraat 49–box 1041, 3000 Leuven, Belgium
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KU Leuven, Biocrystallography, Department of Pharmaceutical and Pharmacological Sciences, Herestraat 49–box 822, 3000 Leuven, Belgium
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Pledge Therapeutics, Gaston Geenslaan 1, 3001 Leuven, Belgium
*
Author to whom correspondence should be addressed.
Academic Editor: Sung-Kun Kim
Int. J. Mol. Sci. 2021, 22(4), 1750; https://doi.org/10.3390/ijms22041750
Received: 18 January 2021 / Revised: 4 February 2021 / Accepted: 6 February 2021 / Published: 10 February 2021
(This article belongs to the Special Issue Enzymes as Targets for Drug Development 2020)
Aminoacyl-tRNA synthetases (aaRSs) catalyze the esterification of tRNA with a cognate amino acid and are essential enzymes in all three kingdoms of life. Due to their important role in the translation of the genetic code, aaRSs have been recognized as suitable targets for the development of small molecule anti-infectives. In this review, following a concise discussion of aaRS catalytic and proof-reading activities, the various inhibitory mechanisms of reported natural and synthetic aaRS inhibitors are discussed. Using the expanding repository of ligand-bound X-ray crystal structures, we classified these compounds based on their binding sites, focusing on their ability to compete with the association of one, or more of the canonical aaRS substrates. In parallel, we examined the determinants of species-selectivity and discuss potential resistance mechanisms of some of the inhibitor classes. Combined, this structural perspective highlights the opportunities for further exploration of the aaRS enzyme family as antimicrobial targets. View Full-Text
Keywords: antimicrobial resistance; aminoacyl-tRNA synthetases; anti-infective targets; structure-based drug design; intermediate analogs; albomycin; microcin C; antibiotic; antibacterial; antifungal antimicrobial resistance; aminoacyl-tRNA synthetases; anti-infective targets; structure-based drug design; intermediate analogs; albomycin; microcin C; antibiotic; antibacterial; antifungal
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MDPI and ACS Style

Pang, L.; Weeks, S.D.; Van Aerschot, A. Aminoacyl-tRNA Synthetases as Valuable Targets for Antimicrobial Drug Discovery. Int. J. Mol. Sci. 2021, 22, 1750. https://doi.org/10.3390/ijms22041750

AMA Style

Pang L, Weeks SD, Van Aerschot A. Aminoacyl-tRNA Synthetases as Valuable Targets for Antimicrobial Drug Discovery. International Journal of Molecular Sciences. 2021; 22(4):1750. https://doi.org/10.3390/ijms22041750

Chicago/Turabian Style

Pang, Luping, Stephen D. Weeks, and Arthur Van Aerschot. 2021. "Aminoacyl-tRNA Synthetases as Valuable Targets for Antimicrobial Drug Discovery" International Journal of Molecular Sciences 22, no. 4: 1750. https://doi.org/10.3390/ijms22041750

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