Antibiotics That Block Bacterial Protein Biosynthesis

This chapter deals with the various classes of antibiotics that exert their bacteriostatic or bactericidal action by blockade of one or more of the protein biosynthetic steps that occur on the 30S and 50S subunits of the bacterial ribosome. It presents a summary on the ribosome and then analyzes the sites and mechanism of action of ribosome-inhibiting antibiotics. The peptidyl chain is translocated onto the aminoacyl-tRNA in the A site by the peptidyltransferase activity in each peptide-chain-elongation cycle of the ribosome. Architectural differences in the 23S RNA of bacterial ribosomes versus their eukaryotic counterparts provide selectivity for killing of the bacteria. The recent X-ray analysis of macrolide antibiotics bound to bacterial ribosomes gives some insight into this selectivity. The determination of the structure of the 30S ribosomal subunit from Thermus thermophilus with bound drug has revealed a major binding site and a lower-affinity binding site for tetracycline. Aminoglycosides are potent drugs against gram-negative bacteria but not very effective against gram-positive organisms, although the combination of aminoglycosides and β-lactams is used to treat enterococcal infections. It has been reported that linezolid-resistant mutants map to the 23S rRNA sites near the peptidyltransferase center, consistent with recent kinetic studies showing that oxazolidinones are competitive inhibitors of both A-site and P-site substrates.