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Inhibitors of Binding of aa-tRNA to the A Site

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Tetracycline was one of the first antibiotics identified. It may inhibit translation by allowing the aa-tRNA–EF-Tu complex to bind to the A site of the ribosome and allowing the GTP on EF-Tu to be cleaved to GDP, but then inhibiting the next step, causing a futile cycle of binding and release of the aa-tRNA from the A site.

Tetracycline has been a very useful antibiotic for treating bacterial diseases, although it is somewhat toxic to humans because it also inhibits the eukaryotic translation apparatus. Unfortunately, overuse has led to the spread of resistance, and it is no longer useful against many infections. In some types of bacteria, ribosomal mutations confer low levels of resistance to tetracycline by changing protein S10 of the ribosome. However, most clinically important resistance to tetracycline and its derivatives is acquired on plasmids and transposons. One of these genes, tetM, carried by Tn916 and its relatives (see chapter 5), encodes an enzyme that confers resistance by methylating certain bases in the 16S rRNA. Other tetracycline resistance genes, such as the tet genes carried by transposon Tn10 and plasmid pSC101 of E. coli, confer resistance by pumping tetracycline out of the cell. One of the more interesting types of resistance to tetracyclines is due to the so-called ribosome protection proteins, represented by TetO and TetQ, which bind to the A site of the ribosome and release tetracycline from its binding site. This is the type of resistance exhibited by the soil bacteria that make tetracycline.

Snyder and Champness Molecular Genetics of Bacteria

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