## 6 Targeting tRNAs in the Ribosome  
There exist three tRNA binding sites on the ribosome: an A-site for the incoming aminoacylated tRNAs, a P-site for the peptidyl-tRNAs and an E site where the deacylated tRNAs exit. The tRNA species bound to these sites adopt a large number of different conformations during the three-stage translation process of initiation, elongation, and termination. As a consequence of this highly complex and essential process, there exists a vast array of natural and synthetic drugs that target different stages of the process binding to the ribosome. Many of these toxins directly interact or interfere with tRNA species in mechanisms ranging from prevention of tRNA anticodon loop binding to mRNA in the decoding center to prevention of aminoacyl-tRNA movement into the P-site the peptidyl transferase center (PTC). The space available in the article limits the detail in which we discuss the large number of antibiotics targeting the ribosome but we direct the reader to a number of excellent reviews recently written on the topic [130, 131, 132, 133]. Initiation of protein synthesis involves, the formation the 70S subunit of the ribosome along with the initiator fMet-tRNA and start codon of mRNA positioned at the P-site. Drugs that inhibit this step are broadly classified either as 50S or 30S inhibitors. Examples of antibiotics binding to the 50S subunit of the ribosome include macrolide (e.g., erythromycincin) [134], limcosamide (e.g., clindamycin) [135, 136], streptogramin (e.g., dalfopristin), amphenicol (e.g., chloramphenicol) and oxazolidine (e.g., linezolid) classes of antibiotics [137]. These include inhibitors that prevent the binding of the initiator tRNA at the P-site (e.g., oxazolidines) [138, 139, 140] and antibiotics that prevent peptide bond formation and/or the translocation of tRNA from the A-site to the P-site on the ribosome (e.g., macrolide, limcosamide and streptogramin class of antibiotics) [141, 142]. This eventually leads to interference with the elongation step and thus the inhibition of protein translation. Similarly, antibiotics inhibiting the 30S subunit include tetracyclines and aminocyclitols (made up of aminoglycos and spectinomycin). Tetracyclines bind to the 30S subunit and block the binding of aminoacylated tRNAs to the A-site of the ribosome [143, 144]. Spectinomycins bind the elongation factor and thereby prevent the binding of peptidyl-tRNAs [145, 146]. Aminoglycos (e.g., streptomycin, gentamycin and kanamycin) bind to the 16S rRNA component of the 30S subunit. Binding results in alteration of the interaction between the mRNA codon and the ribosome, thereby affecting the binding interaction of the incoming aa-tRNAs [147, 148]. This results in generation of mistranslated proteins that are toxic to the cell. Since aminoglycos intake can result in production of toxic proteins, this can affect cell wall and cell membrane compositions, thereby increasing the membrane permeability and subsequently increasing uptake of the drug in the cell [149, 150] (although uptake is limited under anaerobic conditions). Hence aminoglycos are bactericidal, while most of the protein translation inhibitors are bacteriostatic. Aminoglycos also include the 2-deoxy streptamine class of antibiotics (e.g., neomycin, paramomycin, dibekacin and amicakin). These drugs are potent inhibitors of the translocation reaction and they also prevent subunit separation during ribosome recycling [151]. Additionally, these they cause errors in translation by stabilizing the binding of non-cognate tRNAs to the mRNA [137, 147]. Other examples of antibiotics binding to the 30S subunit include tuberactinomycins, thermorubins (Figure 3) and blasticidin S (Figure 3). Tuberactinomycins (e.g., viomycin and capreomycin) are natural antibiotics that bind the interface of the 30S and 50S subunit of the ribosome and thereby inhibit translocation. These drugs have been used for the treatment of _Mycobacterium tuberculosis_ infections including the multi-drug resistant types [152, 153, 154].