Aminoacyl-tRNA Synthetases as Valuable Targets for Antimicrobial Drug Discovery

Int J Mol Sci. 2021 Feb 10;22(4):1750. doi: 10.3390/ijms22041750.


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.

Keywords: albomycin; aminoacyl-tRNA synthetases; anti-infective targets; antibacterial; antibiotic; antifungal; antimicrobial resistance; intermediate analogs; microcin C; structure-based drug design.

Publication types

  • Review

MeSH terms

  • Amino Acids / metabolism
  • Amino Acyl-tRNA Synthetases / antagonists & inhibitors*
  • Amino Acyl-tRNA Synthetases / chemistry
  • Amino Acyl-tRNA Synthetases / metabolism
  • Animals
  • Anti-Infective Agents / chemistry
  • Anti-Infective Agents / pharmacology*
  • Binding Sites / drug effects
  • Drug Discovery*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Targeted Therapy


  • Amino Acids
  • Anti-Infective Agents
  • Enzyme Inhibitors
  • Amino Acyl-tRNA Synthetases