It is established that macrolides, lincosamides, tetracyclines, glycylcyclines, aminoglycosides, and chloramphenicol can inhibit protein synthesis in bacteria. The precise mechanisms of action differ among these classes of drugs.

Whereas bacteria have 70S ribosomes, mammalian cells have 80S ribosomes. The subunits of each type of ribosome, their chemical composition, and their functional specificities are sufficiently different to explain why antimicrobial drugs can inhibit protein synthesis in bacterial ribosomes without having a major effect on mammalian ribosomes.

In normal microbial protein synthesis, the mRNA message is simultaneously “read” by several ribosomes that are strung out along the mRNA strand. These are called polysomes.

Aminoglycosides

 The mode of action of streptomycin has been studied far more intensively than that of other aminoglycosides, but all act similarly. The first step is the attachment of the amino glycoside to a specific receptor protein (P 12 in the case of streptomycin) on the 30S subunit of the microbial ribosome. Second, the aminoglycoside blocks the normal activity of the “initiation complex” of peptide formation (mRNA + formyl methionine + tRNA). Third, the mRNA message is misread on the “recognition region” of the ribosome; consequently, the wrong amino acid is inserted into the peptide, resulting in a nonfunctional protein. Fourth, aminoglycoside attachment results in the breakup of polysomes and their separation into monosomes incapable of protein synthesis. These activities occur more or less simultaneously, and the overall effect is usually an irreversible event—killing of the bacterium.

Chromosomal resistance of microbes to aminoglycosides principally depends on the lack of a specific protein receptor (modification of the target site caused by mutations) on the 30S subunit of the ribosome. Plasmid-dependent resistance to aminoglycosides depends on the production by the microorganism of adenylating, phosphorylating, or acetylating enzymes that destroy the drugs (most common mechanism). A third type of resistance consists of a “permeability defect,” an outer membrane change that reduces active transport of the aminoglycoside into the cell so the drug cannot reach the ribosome. Often this is plasmid mediated.

Macrolides and Ketolides

These drugs (erythromycin, azithromycin, clarithromycin, fidaxomicin, and the ketolide telithromycin) bind to the 50S subunit of the ribosome, and the binding site is domain V of the 23S rRNA. They may interfere with formation of initiation complexes for peptide chain synthesis or may interfere with aminoacyl translocation reactions. Some macrolide-resistant bacteria lack the proper receptor on the ribosome (through methylation of the 23S rRNA target site). The erm (erythromycin ribosome methylation) genes that encode this mechanism may be under plasmid or chromosomal control. They may be expressed constitutively or may be induced by subinhibitory concentrations of macrolides. Other less common mechanisms of resistance include pro duction of inactivating enzymes or mef- and msr-encoded efflux. Efflux-mediated resistance does not affect susceptibility to ketolides.

Lincosamides

Clindamycin and lincomycin bind to the 50S subunit of the microbial ribosome and resemble macrolides in binding site, antibacterial activity, and mode of action. Chromosomal mutants are resistant because they lack the proper binding site on the 50S subunit.

Tetracyclines

Tetracyclines bind reversibly to the 30S subunit of microbial ribosomes. They inhibit protein synthesis by blocking the attachment of charged aminoacyl-tRNA. Thus, they prevent introduction of new amino acids to the nascent peptide chain. The action is usually inhibitory and reversible upon withdrawal of the drug. Resistance to tetracyclines occurs by multiple mechanisms—efflux, ribosomal protection proteins, and chemical modification, among others.

The first two are the most important and occur as follows: Efflux pumps, located in the bacterial cell cytoplasmic membrane, are responsible for pumping the drug out of the cell. Tet gene products are responsible for protecting the ribosome, likely through mechanisms that induce conformational changes. These conformational changes either prevent binding of the tetracyclines or cause their dissociation from the ribosome. This is often plasmid controlled. Mammalian cells do not actively concentrate tetracyclines.

Glycylcyclines

The glycylcyclines are synthetic analogues of the tetracyclines. The agent that is available for use in the United States and Europe is tigecycline, a derivative of minocycline. The glycylcyclines inhibit protein synthesis in a manner similar to the tetracyclines but they demonstrate more avid binding to the ribosome. Tigecycline is active against a broad range of Gram-positive and Gram-negative bacteria, including strains resistant to the typical tetracyclines. This drug has approved indications for treatment of skin and skin structure infections, in intra-abdominal infections and for the treatment of community-acquired pneumonia, particularly those caused by bacterial pathogens resistant to a variety of other antimicrobial agents. In addition, use of this drug for treatment of multidrug-resistant health care-associated infections (except P. aeruginosa) has substantially increased. In 2013, the FDA issued a warning based upon an analysis of 13 clinical trials that demonstrated an increased risk of death with tigecycline (https://www.accessdata.fda.gov/ drugsatfda_docs/label/2013/021821s026s031lbl.pdf). It is suggested that this drug be reserved for situations where other agents are not available or cannot be used because of resistance.

Chloramphenicol

Chloramphenicol binds to the 50S subunit of the 70S bacterial ribosome. It interferes with the binding of new amino acids to the nascent peptide chain, largely because chloramphenicol inhibits peptidyl transferase. Chloramphenicol is mainly bacteriostatic, and growth of microorganisms resumes when the drug is withdrawn. Microorganisms resistant to chloramphenicol usually produce the chloramphenicol acetyl transferases, which destroys drug activity. The production of this enzyme is usually under the control of plasmid-mediated resistance genes called cat genes. Other mechanisms of resistance include efflux pumps and decreased membrane permeability.

Streptogramins

Quinupristin–dalfopristin is a combination of two pristinamycin derivatives. These two agents act synergistically to achieve bactericidal activity against Gram-positive bacteria not seen with either agent alone. The mechanism of action appears to be irreversible binding to different sites on the 50S subunits of the 70S bacterial ribosomes. Resistance may occur from conformational changes in the target, efflux, and enzymatic inactivation.

Oxazolidinones

 The oxazolidinones possess a unique mechanism of inhibition of protein synthesis primarily in Gram-positive bacteria. These compounds interfere with translation by inhibiting the formation of N-formyl-methionyl-tRNA, the initiation complex at the 23S ribosome. Linezolid was the first agent to become commercially available and it has seen widespread usage in the treatment of a variety of serious Gram-positive infections including those caused by vancomycin-resistant enterococci and even mycobacterial infections. The second oxazolidone to become available is tedizolid phosphate, tedizolid is similar in spectrum of activity, mechanism of action, and pharmacology to linezolid.

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مواضيع ذات صلة

Glycopeptides, Lipopeptides, Lipoglycopeptides antibiotics

Macrolides

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Other β-Lactam Drugs

Cephalosporins

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