The antimicrobial drugs reviewed in this chapter selectively inhibit bacterial protein synthesis. The mechanisms of protein synthesis in microorganisms are not identical to those of mammalian cells. Bacteria have 70S ribosomes, whereas mammalian cells have 80S ribosomes. Differences exist in ribosomal subunits and in the chemical composition and functional specificities of component nucleic acids and proteins. Such differences form the basis for the selective toxicity of these drugs against microorganisms without causing major effects on protein synthesis in mammalian cells.
INHIBITORS OF MICROBIAL PROTEIN SYNTHESIS
Drugs that inhibit protein synthesis vary considerably in terms of chemical structures and their spectrum of antimicrobial activity. Chloramphenicol, tetracyclines, and the aminoglycosides (see Chapter 45) were the first inhibitors of bacterial protein synthesis to be discovered. Because they had a broad spectrum of antibacterial activity and were thought to have low toxicities, they were overused. Many once highly susceptible bacterial species have become resistant, and most of these drugs are now used for more selected targets. Erythromycin, an older macrolide antibiotic, has a narrower spectrum of action but continues to be active against several important pathogens. Azithromycin and clarithromycin, semisynthetic macrolides, have some distinctive properties compared with erythromycin, as does clindamycin. Newer inhibitors of microbial protein synthesis, which include streptogramins, linezolid, telithromycin, and tigecycline (a tetracycline analog) have activity against certain bacteria that have developed resistance to older antibiotics.
Most of the antibiotics reviewed in this chapter are bacteriostatic inhibitors of protein synthesis acting at the ribosomal level (Figure 44–1). With the exception of tetracyclines, the binding sites for these antibiotics are on the 50S ribosomal subunit. Chloramphenicol inhibits transpeptidation (catalyzed by peptidyl transferase) by blocking the binding of the aminoacyl moiety of the charged transfer RNA (tRNA) molecule to the acceptor site on the ribosome-messenger (mRNA) complex. Thus, the peptide at the donor site cannot be transferred to its amino acid acceptor. Macrolides, telithromycin, and clindamycin, which share a common binding site on the 50S ribosome, also block transpeptidation. Tetracyclines bind to the 30S ribosomal subunit preventing binding of amino acid-charged tRNA to the acceptor site of the ribosome-mRNA complex.
Steps in bacterial protein synthesis and targets of several antibiotics. Amino acids are shown as numbered circles. The 70S ribosomal mRNA complex is shown with its 50S and 30S subunits. In step 1, the charged tRNA unit carrying amino acid 6 binds to the acceptor site on the 70S ribosome. The peptidyl tRNA at the donor site, with amino acids 1 through 5, then binds the growing amino acid chain to amino acid 6 (transpeptidation, step 2). The uncharged tRNA left at the donor site is released (step 3), and the new 6-amino acid chain with its tRNA shifts to the peptidyl site (translocation, step 4). The antibiotic-binding sites are shown schematically as triangles. Chloramphenicol (C) and macrolides (M) bind to ...
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