That Inhibit Bacterial Protein Synthesis Aminoglycosides

Mechanism of Action An aminoglycoside that binds directly to the 303 ribosomal subunits causing a faulty peptide sequence to form in the protein chain. Therapeutic Effect Inhibits bacterial protein synthesis. 

The aminoglycosides penetrate the bacterial plasma membrane in a complex and individual way, described in Section 14.3. They act by inhibiting protein synthesis at an early stage. While harmless to the mammalian (805) ribosome, they bind to the 305 subunit of the bacterial ribosome (Le Goffic etal., 1979) and are actually bactericidal, whereas other antibiotics that interfere with protein synthesis are only bacteriostatic. 

The selection of transformed chloroplasts usually involves the use of an antibiotic resistance marker. Spectinomycin is used most routinely because of the high specificity it displays as a prokaryotic translational inhibitor as well as the relatively low side effects it exerts on plants. The bacterial aminoglycoside 3 -adenyltransferase gene (ciadA) confers resistance to both streptomycin and spectinomycin. The aadA protein catalyzes the covalent transfer of an adenosine monophosphate (AMP) residue from adenosine triphosphate (ATP) to spectinomycin, thereby converting the antibiotic into an inactive form that no longer inhibits protein synthesis for prokaryotic 70S ribosomes that are present in the chloroplast. 

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. 

The mechanism of protein synthesis inhibition exhibited by aminoglycosides other than SM differ in particular details. It was shown that KM, NM, and GM have multiple ribosomal binding sites rather than the single site to which SM binds. Translocation on bacterial ribosomes is also inhibited by these agents. 

Spectinomycin selectively inhibits protein synthesis in Gram-negative bacteria. The antibiotic binds to and acts on the 30S ribosomal subunit (see also Figure 75). Its action has similarities to that of the aminoglycosides however, spectinomycin is not bactericidal and does not cause misreading of polyribonucleotides. A high degree of bacterial resistance may develop as a result of mutation. 

Aminoglycosidic antibioties inhibit protein synthesis on bacterial ribosomes, but the primary sites that are subject to the action of each of these antibiotics are different and are now under study. As yet, there is no information about the chemical structure of the primary sites, and... 

Many drugs that inhibit protein synthesis are able to distinguish between bacterial and eukaryotic ribosomes, even in intact cells. This is illustrated in Fig. 5.6. The aminoglycoside antibiotics, such as streptomycin, bind to the 305 subunit exclusively, whereas chloramphenicol and erythromycin bind only to the 505 subunit. Through having no affinity for the host s 805 ribosomes, these... 

Viomycin has been shown to inhibit protein synthesis but not to cause codon misreading in the bacterial ribosomal system. Thus, the base properties of antibiotics alone seem not to be enough to cause miscoding, which confirms the notion that streptamine or deoxystreptamine moieties of aminoglycoside antibiotics are essential for miscoding activity. 

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