## 1 Introduction  
tRNAs are the key decoding adaptors in the protein synthesis machinery that allows the mRNA genetic code to be translated into a linear sequence of amino acids in a polypeptide chain [1, 2]. There are numerous tRNA isoacceptors for each of the canonical 20 amino acids designated by the genetic code [3]. These tRNA species show a significant variety in both base sequence and modifications in both prokaryotes and eukaryotes while still maintaining the ability to bind to the highly conserved ribosome active sites [4]. This essential and ubiquitous nature of tRNAs in protein synthesis make them prime targets for antibiotics with a vast array of natural and synthetic inhibitors that interfere with these components of protein translation. The targeting of these antibiotics is not simply restricted to tRNAs and aminoacyl-tRNAs bound to the ribosome but all the biological processing and tailoring stages that are required to make the aminoacyl-tRNA substrates. tRNAs have also been found to play diverse roles in the cell, such as cell wall biosynthesis, cell membrane permeability and antibiotic persistence, which can also be targeted by antibiotics [5,6]. The purpose of this review then is to describe these tRNA targeting antibiotics and their mechanisms. This may provide more insights into approaches that could be undertaken to design novel anti-infectives for the treatment of diseases. Figure 1: Stages of tRNA biology and protein biosynthesis in bacteria targeted by antibiotics. **(a)** Pre-tRNA transcripts are first processed by ribonucleases (RNase) E or F at the 3’-end, followed by RNase D. Similarly, the 5’-leader sequence is acted upon by RNase P, which is followed by nucleotidyltransferases (NT) for addition of CCA at the 3’-trailer sequence; **(b)** Modification of certain bases takes place using tRNA modification enzymes (mostly in the anticodon stem loop domain) to produce **(c)** the mature tRNA; **(d)** Aminoacyl-tRNA synthetases add amino acids to the cognate tRNA at the CCA 3’-end; **(e)** Activated EF-Tu-GTP complex recognizes the aminoacylated tRNA and transports it to the A-site on the 30S ribosomal subunit; **(f)** Once assembly of the mRNA, fMet-tRNAMet and 50S subunit is complete, the peptidyl transferase reaction starts and initiates the building of the polypeptide chain. Once the ribosome encounters a stop codon, the addition of amino acids to the polypeptide chain halts and the complete polypeptide chain is released; and **(g)** Deacylated tRNA then exits the ribosome at the E site and the ribosome once again dissociates into 30S and 50S subunits. Examples of some antibiotics are shown that inhibit each of these different stages from **(a)** to **(g)**. In order to fulfill their roles in protein synthesis, tRNA transcripts have to be extensively processed by an assortment of enzymes and ribonucleoprotein complexes (Figure 1). The process of tRNA maturation involves five main steps: (a) Removal of the 5' leader sequence from the tRNA; (b) removal of the 3'-trailer sequence by RNase E or F followed by RNase D; (c) Addition of the CCA 3'-end by tRNA nucleotidyl transferases (or repair of this region for those tRNA genes that encode the CCA 3'-end); and (d) Modification of tRNA, such as methylation of tRNA bases, to assist in folding, addition of dihydroxyuridine in the D-loop and addition of pseudouridine in the T\(\psi\)C loop. A majority of modifications take place in the anticodon stem loop as detailed later. Mature tRNAs then have to be ligated to the correct amino acid catalyzed by the aminoacyl tRNA synthetase (aaRS) family of enzymes [7] (Figure 1). AaRSs all catalyze the tRNA aminoacylation reaction in two steps. Firstly, each canonical amino acid reacts with ATP to form an enzyme bound aminoacyl-adenylate intermediate and inorganic pyrophosphate.