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Protein Synthesis -Translation and Regulation

Clostridium sordellii and C. septicum posses susceptibility similar to C. perfringens, although there are occasional strains resistant to extended spectrum penicillins and clindamycin. Clostridium tertium displays resistance to third generation cephalosporins (83% resistance to ceftriaxone) (, , ). Resistance was also found to cefoxitin (17%), cefotetan ( 17%), and clindamycin (7%) (). Decreased affinity for penicillin-binding proteins was found for strains of C. perfringens and beta lactamase production has been observed with C. ramosum, C. butyricum and C. clostridioforme. A transferable plasmid mediated resistance to tetracycline, chloramphenicol and erythromycin-clindamycin was observed with C. perfringens.
In vivo studies demonstrated that drugs other than penicillin were more effective in treatment of Clostridial infection. Clindamycin, metronidazole, rifampin and tetracycline were more efficacious than penicillin in the treatment of fulminate gas gangrene in mice caused by C. perfringens (). Protein synthesis inhibitors (tetracycline, metronidazole, rifampin, clindamycin and chloramphenicol) were found to be better inhibitors of toxin synthesis than cell wall active agents (penicillin). A combined superior rapid bacterial killing and ability to suppress toxin production was noted with clindamycin, rifampin and metronidazole, as compared to penicillin ().

Inhibition of polyuridylic acid‐induced ribosomal protein synthesis by chloramphenicol

Chloramphenicol inhibits translation in bacterial cells, intact chloroplasts, and intact mitochondria. Some of the toxic side effects associated with chloramphenicol may arise from the effect of the drug on mitochondrial metabolism. Translation by mammalian cells, yeast, and protozoa is not inhibited by chloramphenicol.

PROTEIN SYNTHESIS INHIBITORS Chapter:11 ..

The 5' cap present on all eukaryoticmRNAs seems to be the first signal to start protein synthesis.

The cytotoxic potential of chloramphenicol with regard to cell membrane function was examined in a study investigating inhibition of protozoan motility. The effect of chloramphenicol on the locomotion of the protozoan , a model widely used for the evaluation of toxicity in excitable tissue, was tested. Chloramphenicol appeared to depress the motility of the test organism more effectively than did chloramphenicol succinate, the hydrophilic form of chloramphenicol. Results suggested that chloramphenicol, with its hydrophobic free form, has the ability to partition into the lipid bilayer of the cell membrane and thus the potential to cause membrane-mediated toxic effects. The authors postulated that such effects might explain the acute toxicity of chloramphenicol in excitable tissues, such as myocardium, and are a possible mechanism for chloramphenicol-induced cardiovascular collapse in neonates, or "grey baby syndrome" (Wu et al., 1996).

Inhibition of protein synthesis in the mitochondria of bone-marrow cells has been considered as a mechanism by which bone-marrow depression is induced by chloramphenicol. The underlying cytotoxicity may be caused by the similarity between mitochondrial ribosomes and bacterial ribosomes, both of which are 70S. Thus chloramphenicol can also inhibit mitochondrial protein synthesis in mammalian cells, particularly in erythropoietic cells, which appear to be sensitive to the drug (Sande & Mandell, 1993; Kucers et al., 1997). It was reasoned that the inhibition of mitochondrial protein synthesis suppressed the division of mitochondria and resulted in the formation of megamitochondria. Investigation of the toxicity caused by chloramphenicol in mouse hepatic cells in vivo, however, showed that antioxidants prevented the formation of megamitochondria (Matsuhashi et al., 1996). The role of antioxidants in reducing the cytotoxic effects of chloramphenicol was also reported to occur in vitro in a study using a monkey kidney-derived cell line and haematopoietic progenitor cells from human neonatal cord blood. Also, in cells in culture, the cytotoxic effects of chloramphenicol on apoptosis and suppression of progenitor cell growth were not pronounced when cells were co-cultured with antioxidants such as mercaptoethylamine or vitamin C (Holt et al., 1997). Both studies suggested that toxicity caused by chloramphenicol relates intimately to oxidative stress, with a possible link between a metabolic event—the production of free radicals—and bone marrow suppression.

Antibiotics that Inhibit Bacterial Protein Synthesis

Effect of some antibiotics on the protein synthesis in cell suspensions and on the peptidyl transferase in cell‐free systems

Chloramphenicol inhibits protein synthesis in bacterial extracts with varying potencies depending on the template employed. In particular, synthesis promoted by poly(U) is markedly more resistant to chloramphenicol than that promoted by poly(C) or poly (A) (8). Synthesis occurring with a natural mRNA (eg, MS2 phage RNA) is usually very sensitive to chloramphenicol. The precise reason for the template-dependence is not known. Chloramphenicol may inhibit poly(U)-dependent poly(Phe) synthesis less than it does the synthesis of other polypeptides because the structures of D-threo chloramphenicol and L-phenylalanine are similar (Fig. 3). Competition between these molecules during poly(Phe) synthesis may involve steric hindrance between their phenyl groups and, consequently, chloramphenicol may be chased from the ribosome. Nevertheless, this does not explain why the same template dependence is also observed with several other peptidyl-transferase inhibitors that differ chemically from chloramphenicol and, in particular, that do not have a phenyl group (e.g, the group B streptogramins and the macrolides). Further experiments are needed to elucidate this phenomenon in greater detail.

The peptidyl-transferase assay in which peptide bonds are formed between a peptidyl-tRNA and puromycin on the 50S subunit (the "puromycin reaction") has been used to unravel the mechanism of action of chloramphenicol (6) (Fig. 2). Chloramphenicol blocks this reaction, provided that the donor peptidyl-tRNA, bound at the P site, is short (eg, AcPhe-tRNA). In this case, chloramphenicol appears to disturb the correct positioning of the nascent peptide during its synthesis, thereby causing the premature release of the peptidyl-tRNA from the ribosome. Chloramphenicol does not, however, affect the puromycin reaction when a larger peptidyl-tRNA—for example, Ac(Phe)2-tRNA—is used as donor (7). It is likely, therefore, that chloramphenicol interferes with the binding of the terminal CCA of the aminoacyl-tRNA at the A site and also interferes with the entry of the nascent polypeptide into the "tunnel" that normally guides it away from the peptidyl-transferase center.

The 5’ UTRs of most mRNAs contain a consensus sequence of5’-CCAGCCAUG-3’ involved in the initiation of protein synthesis.
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with the 30S ribosome subunit to inhibit protein synthesis

The aminoglycosides are products of species and are represented by streptomycin, kanamycin,tobramycin and gentamicin. These antibiotics exert theiractivity by binding to bacterial ribosomes and preventing theinitiation of protein synthesis.

How does chloramphenicol inhibit protein synthesis

Streptomycin binds to 30S subunit of the bacterial ribosome,specifically to the S12 protein which is involved in the initiation ofprotein synthesis. Experimentally, streptomycin has been shown toprevent the initiation of protein synthesis by blocking the binding ofinitiator N-formylmethionine tRNA to the ribosome. It also prevents thenormal dissociation of ribosomes into their subunits, leaving themmainly in their 70S form and preventing the formation of polysomes. Theoverall effect of streptomycin seems tobe one of distorting the ribosome so that it no longer can carry outitsnormal functions. This evidently accounts for its antibacterialactivitybut does not explain its bactericidal effects, which distinguishesstreptomycinand other aminoglycosides from most other protein synthesis inhibitors.


• Chloramphenicol inhibits the synthesis of

Kanamycin and tobramycin have been reported to bindto the ribosomal 30S subunit and to prevent it from joining to the 50Ssubunitduring protein synthesis. They may have a bactericidal effect becausethisleads to cytoplasmic accumulation of dissociated 30S subunits, which isapparently lethal to the cells.

INHIBITION OF PROTEIN SYNTHESIS IN MAMMALIAN …

The tetracyclines consist of eight related antibiotics whichare all natural products of , although some can nowbe produced semisynthetically or synthetically. Tetracycline, chlortetracyclineand doxycycline are the best known. The tetracyclines arebroad-spectrum antibiotics with a wide range of activity against bothGram-positive and Gram-negative bacteria. is less sensitive but is generally susceptible to tetracyclineconcentrations that are obtainable in the bladder. The tetracyclinesact by blocking the binding of aminoacyl tRNA to the A site on theribosome. Tetracyclines inhibit protein synthesis on isolated 70S or80S (eucaryotic) ribosomes, and in both cases, their effect is on thesmall ribosomal subunit. However, most bacteria possess an activetransport system for tetracycline that will allow intracellularaccumulation of the antibiotic at concentrations 50 times as great asthat in the medium. This greatly enhances its antibacterialeffectiveness and accounts for its specificity of action, since aneffective concentration cannot be accumulated in animal cells. Thus ablood level of tetracycline which is harmless toanimal tissues can halt protein synthesis in invading bacteria.

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