Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 4, Pages -Publisher
MDPI
DOI: 10.3390/ijms22041750
Keywords
antimicrobial resistance; aminoacyl-tRNA synthetases; anti-infective targets; structure-based drug design; intermediate analogs; albomycin; microcin C; antibiotic; antibacterial; antifungal
Funding
- Research Foundation-Flanders (Fonds voor Wetenschappelijk Onderzoek) [G077814N, G0A4616N]
- KU Leuven Research Fund [G0A4616N, 3M14022]
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Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes in all three kingdoms of life, and have been recognized as suitable targets for small molecule anti-infectives. This review discusses the catalytic activities of aaRSs, inhibitory mechanisms, and species-selectivity determinants of reported inhibitors. The structural perspective highlights opportunities for further exploration of the aaRS enzyme family as antimicrobial targets.
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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