Role of Aminoacyl-tRNA Synthetases in Infectious Diseases and Targets for Therapeutic Development

Abstract

Aminoacyl-tRNA synthetases (AARSs) play a pivotal role in protein synthesis and cell viability. These 22 "housekeeping" enzymes (1 for each standard amino acid plus pyrrolysine and o-phosphoserine) are specifically involved in recognizing and aminoacylating their cognate tRNAs in the cellular pool with the correct amino acid prior to delivery of the charged tRNA to the protein synthesis machinery. Besides serving this canonical function, higher eukaryotic AARSs, some of which are organized in the cytoplasm as a multisynthetase complex of nine enzymes plus additional cellular factors, have also been implicated in a variety of non-canonical roles. AARSs are involved in the regulation of transcription, translation, and various signaling pathways, thereby ensuring cell survival. Based in part on their versatility, AARSs have been recruited by viruses to perform essential functions. For example, host synthetases are packaged into some retroviruses and are required for their replication. Other viruses mimic tRNA-like structures in their genomes, and these motifs are aminoacylated by the host synthetase as part of the viral replication cycle. More recently, it has been shown that certain large DNA viruses infecting animals and other diverse unicellular eukaryotes encode tRNAs, AARSs, and additional components of the protein-synthesis machinery. This chapter will review our current understanding of the role of host AARSs and tRNA-like structures in viruses and discuss their potential as anti-viral drug targets. The identification and development of compounds that target bacterial AARSs, thereby serving as novel antibiotics, will also be discussed. Particular attention will be given to recent work on a number of tRNA-dependent AARS inhibitors and to advances in a new class of natural "pro-drug" antibiotics called Trojan Horse inhibitors. Finally, we will explore how bacteria that naturally produce AARS-targeting antibiotics must protect themselves against cell suicide using naturally antibiotic resistant AARSs, and how horizontal gene transfer of these AARS genes to pathogens may threaten the future use of this class of antibiotics.

Aminoacyl-tRNA synthetases, therapeutic targets for infectious diseases

“…Therapeutic applications of ARS-targeted inhibitors will offer the alternative drugs to overcome the inevitable bacterial resistance to currently used antibiotics. Although there are no known antiviral drugs targeting ARSs, identification of a GAIT-like RNA motif in the viral genome [68] or discovery of host ARS-RNA intermediates that are packaged into retroviruses may offer a new opportunities for the development of antiviral agents [148].…”

“…In addition, despite the structural homology, specific sequence differences between prokaryotic and eukaryotic ARSs can be used to design discriminating and specific ARS-targeted drugs. For example, the successful application of mupirocin is derived from a mere two-amino-acid difference between the prokaryotic and eukaryotic ARS [148]. Mutational analysis of amino acid residues will further characterize the critical sites involved in the interactions between ARSs and their inhibitors.…”

“…Introduction of this gene to pathogenic A. tumefaciens imparted antibiotic resistance, suggesting that the biocontrol organism carries a self-protected ARS to avoid cell death [155]. Thus, although ARSs are good drug targets due to their high selectivity and potency toward microbes, sharing of ARS resistance genes not only locally, among neighboring bacteria, but also across long distances by selective pressure is a major obstacle for ARS drug application [148]. Identification of ARS inhibitors that are not associated with self-immunity and that do not transfer natural resistance genes should be identified.…”

Discovery of Small‐Molecule Antibiotics against a Unique tRNA‐Mediated Regulation of Transcription in Gram‐Positive Bacteria

“…New approaches to combat antibiotic resistance include targeting the synthesis of aminoacyl‐tRNA synthetases (aaRS) and charging of tRNA, DNA replication, RNA transcription, the action of topoisomerases and riboswitches that carry out essential bacterial cell functions . Riboswitches are suitable targets for intervention as they have highly selected metabolite receptors located within the 5′‐untranslated region (5′UTR) of messenger RNAs (mRNA) controlling transcription or translation and are validated targets for intervention .…”

Identification of Mycobacterium tuberculosis leucyl-tRNA synthetase (LeuRS) inhibitors among the derivatives of 5-phenylamino-2H-[1,2,4]triazin-3-one

“…Aminoacyl-tRNA synthetases (aaRSs) are promising antiinfective drug targets. These enzymes play pivotal role in protein synthesis and have wide evolutionary divergence in prokaryotes and eukaryotes which allow the development of selective aaRSs inhibitors [1][2][3][4][5][6] .…”