Protein synthesis bacterial, drugs inhibiting

Chloramphenicol is able to inhibit the peptidyl transferase reaction and so bacterial protein synthesis by binding reversibly to the 50s ribosomal subunit. Resistance can occur due to the plasmid-mediated enzyme chloramphenicol acetyltransferase which inactivates the drug by acetylation. Such resistance is often a part of plasmid-mediated multidrug resistance. Resistance can also occur by an altered bacterial permeability. However in most instances resistance to chloramphenicol only develops slowly and remains partial. 

Mechanism of Action A macrolide that binds to ribosomal receptor sites of susceptible organisms, inhibiting bacterial protein synthesis. Therapeutic Effect Bactericidal or bacteriostatic, depending on drug dosage. 

Their antibacterial and mutagenic activity is closely related to the reduction of the 5-nitro group, which is common to all nitroimidazole drugs, and the subsequent formation of reactive metabolites that bind to bacterial DNA, inhibiting DNA and protein synthesis in the microorganisms. Metabolism of 5-nitroimidaz-oles in mammals usually leads to covalently bound residues with a persistent imidazole structure. 

Inhibitors are substances that tend to decrease the rate of an enzyme-catalysed reaction. Although some act on the substrate, the discussion here will be restricted to those inhibitors which combine directly with the enzyme. Inhibitors have many uses, not only in the determination of the characteristics of enzymes, but also in aiding research into metabolic pathways where an inhibited enzyme will allow metabolites to build up so that they are present in detectable levels. Another important use is in the control of infection where drugs such as sulphanilamides competitively inhibit the synthesis of tetrahydrofolates which are vitamins essential to the growth of some bacteria. Many antibiotics are inhibitors of bacterial protein synthesis (e.g. tetracyclin) and cell-wall synthesis (e.g. penicillin). 

Drugs That Inhibit Bacterial Protein Synthesis... 

DRUGS THAT INHIBIT BACTERIAL PROTEIN SYNTHESIS... 

Tetracycline and tetracycline derivatives (see Table 33-3) inhibit protein synthesis by binding to several components of the ribosomal apparatus in susceptible bacteria.3,12 Hence, these drugs may cause misreading of the mRNA code, as well as impair the formation of peptide bonds at the bacterial ribosome. Thus, tetracyclines are very effective in preventing bacterial protein synthesis. 

Mechanism of Action. Pyrimethamine blocks the production of folic acid in susceptible protozoa by inhibiting the function of the dihydrofolate reductase enzyme. Folic acid helps catalyze the production of nucleic and amino acids in these parasites. Therefore, this drug ultimately impairs nucleic acid and protein synthesis by interfering with folic acid production. The action of sulfadoxine and other sulfonamide antibacterial agents was discussed in Chapter 33. These agents also inhibit folic acid synthesis in certain bacterial and protozoal cells. 

The drugs described in this chapter all share the property of inhibiting bacterial protein synthesis by binding to and interfering with their ribosomes. 

Entry of these agents into susceptible organisms is mediated by transport proteins unique to the bacterial inner cytoplasmic membrane. Binding of the drug to the 30S subunit of the bacterial ribosome is believed to block access of the amino acyl-tRNA to the mRNA-ribosome complex at the acceptor site, thus inhibiting bacterial protein synthesis.2... 

The drug binds to the bacterial 50S ribosomal subunit and inhibits protein synthesis at the peptidyl transferase reaction. Because of the similarity of mammalian mitochondrial ribosomes to those of bacteria, protein synthesis in these organelles may be inhibited at high circulating chloramphenicol levels, producing bone marrow toxicity. 

Chloramphenicol blocks translation in bacteria by inhibiting peptidyltransferase of the large ribosomal subunit. It does not interfere with peptidyltransferase in the large subunit of eukaryotic ribosomes. However, the mitochondrion of animal cells contains ribosomes that are similar to bacterial ribosomes, and chloramphenicol can block protein synthesis in this organelle. This could contribute to the side effects of this drug when used in the treatment of animals. 

Many antibiotics kill bacteria by binding to the ribosome and thereby inhibiting protein synthesis. After decades of antibiotic use, many pathogens have become resistant to antibiotics, and thus ne v antibiotics are needed to treat bacterial diseases. Rational drug design is expected to play an important role in meeting this need. 

A third difference between bacterial and human cells involves their ribosomes. Bacterial ribosomes are neither the same size nor have the same composition as human ribosomes. Thus drugs that bind more to bacterial than to human ribosomes can inhibit bacterial protein synthesis and have a selective toxicity for these cells. 

Macrolides inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit and preventing elongation of the peptide chain. These drugs have low toxicity because they do not bind to mammalian ribosomes. 

The mechanism of toxicity for aminoglycosides has not been fully explained and is therefore unclear. It is known that the drug attaches to a bacterial cell wall and is drawn into the cell via channels made up of a protein, porin. Once inside the cell, the aminoglycoside attaches to the 30S bacterial ribosomes. Ribosomes are the intracellular structures responsible for manufacturing proteins. This attachment either inhibits protein biosynthesis or causes the cell to produce abnormal, ineffective proteins. The bacterial cell cannot survive with this impediment. This explanation, however, does not account for the potent bactericidal properties of these agents, since other antibiotics that inhibit the synthesis of proteins (such as tetracycline) are not bactericidal. Recent experimental studies show that the initial site of action is the outer bacterial membrane. The cationic antibiotic molecules create fissures in the outer cell membrane, resulting in leakage of intracellular contents and enhanced antibiotic uptake. This rapid action at the outer membrane probably accounts for most of the bactericidal activity. 

Erythromycin is indicated for the treatment of infections caused by erythromycin susceptible bacteria. The drug binds to the 50 S ribosomal subunit inhibiting bacterial RNA-dependent protein synthesis. Susceptible bacteria include most Gram-positive bacteria and the atypical pathogens. 

An understanding of the biochemistry of peptidoglycan (PG murein) that comprises bacterial cell walls is very important medically since blockage of its synthesis was the first, and continues to be a primary, point of attack in the control of bacterial infection. In addition to inhibition of cell wall synthesis, antimicrobial drug s main mechanisms are interference with nucleic acid synthesis, inhibition of folate metabolism, and binding to ribosomes to disrupt protein synthesis (Table 16-2). 

Which one of the following drugs inhibits bacterial protein synthesis, preventing the translocation step via its interaction with the 50S ribosomal subunit ... 

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