Aminoacyl-tRNA Synthetases as Valuable Targets for Antimicrobial Drug Discovery |
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Authors: | Luping Pang Stephen D Weeks Arthur Van Aerschot |
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Affiliation: | 1.KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Herestraat 49–box 1041, 3000 Leuven, Belgium;2.KU Leuven, Biocrystallography, Department of Pharmaceutical and Pharmacological Sciences, Herestraat 49–box 822, 3000 Leuven, Belgium;3.Pledge Therapeutics, Gaston Geenslaan 1, 3001 Leuven, Belgium; |
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Abstract: | 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. |
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Keywords: | antimicrobial resistance aminoacyl-tRNA synthetases anti-infective targets structure-based drug design intermediate analogs albomycin microcin C antibiotic antibacterial antifungal |
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