Several classes of antibiotics target bacterial protein syn thesis and severely disrupt cellular metabolism. Antibiotic classes that act by inhibiting protein synthesis include aminoglycosides, macrolide-lincosamide-streptogramins (MLS group), ketolides (e.g., telithromycin) chloramphenicol, tetracyclines, glycylglycines (e.g., tigecycline), and oxazolidinones (e.g., linezolid). Although these antibiotics are generally categorized as protein synthesis inhibitors, the specific mechanisms by which they inhibit protein synthesis differ significantly.

Aminoglycosides and Aminocyclitols. Aminoglycosides (aminoglycosidic aminocyclitol) inhibit bacterial protein synthesis by irreversibly binding to protein receptors on the organism’s 30S ribosomal subunit. This process interrupts several steps, including initial formation of the protein synthesis complex, accurate reading of the messenger RNA (mRNA) code, and formation of the ribosomal-mRNA complex. The structure of a commonly used aminoglycoside, gentamicin, is shown in Figure 1. Other aminoglycosides include tobramycin, amikacin, streptomycin, and kanamycin. The spectrum of activity of aminoglycosides includes a wide variety of aerobic gram-negative and certain gram-positive bacteria, such as S. aureus. Bacterial uptake of the aminoglycosides is accomplished by using them in combination with cell wall–active antibiotics, such as β-lactams or vancomycin. Anaerobic bacteria are unable to uptake these agents intracellularly and therefore are typically not inhibited by aminoglycosides. Aminoglycosides are associated with toxicity, and blood levels should be monitored during therapy. The major toxicities are nephrotoxicity and auditory or vestibular toxicity.

Fig1. Structure of the commonly used aminoglycoside gentamicin. Potential sites of modification by adenylating, phosphorylating, and acetylating enzymes produced by bacteria are highlighted.  (Modified from Salyers AA, Whitt DD, editors: Bacterial pathogenesis: a molecular approach, Washington, DC, 1994, ASM Press.)

Macrolide-Lincosamide-Streptogramin (MLS) Group. The most commonly used antibiotics in the MLS group are the macrolides (e.g., erythromycin, azithromycin, clarithromycin, and clindamycin, which is a lincosamide). Protein synthesis is inhibited by drug binding to the 23sRNA on the bacterial 50S ribosomal subunit and sub sequent disruption of the growing peptide chain by blocking of the translocation reaction. Macrolides are generally bacteriostatic, but they may be bactericidal if the infective dose of the organism is low and the drug is used in high concentrations. Primarily because of uptake difficulties associated with the outer membranes of gram-negative bacteria, the macrolides and clindamycin generally are not effective against most genera of gram-negative organ isms. However, they are effective against gram-positive bacteria, mycoplasmas, treponemes, and rickettsiae. Quinupristin-dalfopristin is a dual streptogramin that targets two sites on the 50S ribosomal subunit. Toxicity is generally low with macrolides, although hearing loss and reactions with other medications may occur.

The lincosamides, clindamycin and lincomycin, bind to the 50s ribosomal subunit and prevent elongation by interfering with the peptidyl transfer during protein syn thesis. They may exhibit bacteriocidal or bacteriostatic activity. The spectrum of activity depends on the bacterial species, the size of the inoculum, and the drug concentration. Lincosamides are effective against gram-positive cocci.

Streptogramins are naturally occurring cyclic peptides including quinupristin-dalfopristin. The streptogramins enter the bacterial cells through passive diffusion and bind irreversibly to the 50s subunit of the bacterial ribosome inducing a conformational change in the ribosome structure. Alteration of the ribosome structure interferes with peptide bond formation during protein synthesis, disrupting elongation of the growing peptide. The streptogramins are able to enter most tissues and are effective against gram-positive and some gram-negative organ isms. The drugs have low toxicity; localized phlebitis is the major complication of intravenous infusion.

Ketolides. This group of compounds consists of chemical derivatives of erythromycin A and other macrolides. As such, they act by binding to the 23s rRNA of the 50S ribosomal subunit, inhibiting protein synthesis. The key difference between the only currently available ketolide, telithromycin, and the macrolides is that telithromycin maintains activity against most macrolide resistant gram-positive organisms and does not induce a common macrolide resistance mechanism (i.e., macrolide- lincosamide-streptogramin-B [MLSB] methylase), the alteration of the ribosomal target. Ketolides are effective against respiratory pathogens and intracellular bacteria. The agents are particularly effective against gram-positive and some gram-negative bacteria, as well as Mycoplasma, Mycobacteria, Chlamydia, and Rickettsia spp. and Francisella tularensis. Ketolides have low toxicity, and the major side effect are gastrointestinal symptoms, including diarrhea, nausea, and vomiting.

Oxazolidinones. Oxazolidinones, currently represented by linezolid, are a relatively new class of synthetic antibacterial agents available for clinical use. Linezolid is a synthetic agent that inhibits protein synthesis by specifically interacting with the 23S rRNA in the 50S ribosomal subunit, interfering with the binding of the transfer RNA (tRNA) for formylated-methionine. This action inhibits initiation of translation of any mRNA, thereby preventing protein synthesis. Therefore, linezolid is not expected to be affected by resistance mechanisms that affect other drug classes. Linezolid is effective against most gram-positive bacteria and mycobacteria. Toxicity is generally low, resulting in gastrointestinal symptoms, including diarrhea and nausea.

Chloramphenicol. Chloramphenicol inhibits the addition of amino acids to the growing peptide chain by reversibly binding to the 50S ribosomal subunit, inhibiting transpeptidation. This antibiotic is highly active against a wide variety of gram-negative and gram-positive bacteria; however, its use has dwindled because of drug toxicity and the development of new effective and safer agents, mostly of the beta-lactam class. Bone marrow toxicity is the major side effect associated with chloramphenicol treatment.

Tetracyclines. The tetracyclines are considered broad spectrum bacteriostatic antibiotics. They inhibit protein synthesis by binding reversibly to the 30S ribosomal subunit, interfering with the binding of the tRNA–amino acid complexes to the ribosome, preventing peptide chain elongation. Tetracyclines have a broad spectrum of activity that includes gram-negative bacteria, gram positive bacteria, several intracellular bacterial pathogens (e.g., Chlamydia and Rickettsia spp.), and some protozoa. Infections caused by Neisseria gonorrhoeae, mycoplasma, and spirochetes may be successfully treated with these drugs. Toxicity includes upper gastrointestinal effects, such as esophageal ulcerations, nausea, vomiting, and epigastric distress. In addition, cutaneous photo toxicity may also develop, resulting in disease, including photoallergic immune reactions.

Glycylglycines. These agents are semi-synthetic tetracycline derivatives. Tigecycline is the first agent of this class approved for clinical use. Similar to the tetracyclines, tigecycline inhibits protein synthesis by reversibly binding to the 30S ribosomal subunit. However, tigecycline has the advantage of being refractory to the most common tetracycline resistance mechanisms expressed by gram negative and gram-positive bacteria. The most common side effects are nausea, vomiting, and diarrhea.

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مواضيع ذات صلة

Inhibitors of Cell Membrane Function

Inhibitors of Cell Wall Synthesis

Sulfonamides and Trimethoprim

Quinolones

Aminoglycosides

Glycopeptides, Lipopeptides, Lipoglycopeptides antibiotics

Macrolides

Chloramphenicol

Tetracyclines

Other β-Lactam Drugs

Cephalosporins

Penicillins