Inhibitors of Bacterial Elongation Factor EF-Tu

Decoding of the genetic message occurs in a ribosomal site called A-site. Here, a given amino acid is specifically recognized by the anticodon triplet of a tRNA molecule carrying the corresponding amino acid. In all kingdoms of life, the aminoacyl-tRNA (aa-tRNA) does not bind to the ribosomal A-site in a free form but is always accompanied by an elongation factor (EF) with a bound guanosine- 5-triphosphate (GTP) molecule so that a ternary complex is the molecular form in which all aa-tRNAs, with the exception of the initiator tRNA, are brought to the ribosome. In bacteria, the EF responsible for this activity is EF-Tu, a notable representative of a widespread class of proteins called G proteins. The function of EF-Tu is not restricted to that of a simple carrier insofar as this factor plays, together with the ribosome, an active role in the faithful selection of the correct aa-tRNA. As with other members of the GTPase switch proteins, EF-Tu also undergoes important structural changes when its bound GTP molecule is hydrolyzed to GDP following the activation by the ribosome of the intrinsic GTPase activity of EF-Tu. Upon formation of codon–anticodon interaction, the affinity of EF-Tu·GDP for the ribosome is substantially decreased so that the factor can be dissociated from the ribosome. Unlike the other ribosome-dependent GTPases, IF2, and EF-G, which do not require a GTP–GDP exchange factor, GDP is dissociated from the EF-Tu and exchanged for GTP through the action of EF-Ts [1–3]. The translation elongation steps involved in the EF-Tu-dependent decoding of aa-tRNA are schematically represented in Figure 18.1. EF-Tu is one of the major antibiotic targets among the protein synthesis inhibitors, a property that emphasizes its central role in protein synthesis and cell growth [4]. Four families of antibiotics of unrelated structures have EF-Tu as target. They comprise a total of more than 30 members and have selective antibacterial activities. Their prototypes are enacyloxin IIa, kirromycin, pulvomycin, and GE2270A