Antibiotic protein synthesis inhibitors sensitivity

The response of intestinal calcium transport to vitamin D is sensitive to the pretreatment by actinomycin However, it is unclear whether actinomycin D blocks the intestinal response to 1,25-(OH)2D3 There is some evidence which suggests that the lifetime of the 25-OH-D3-l-hydroxylase and its messenger is sufficiently short that the apparent block in vitamin D action on intestinal calcium transport may be due to the decay of the messenger and of the enzyme for the 1-hydroxylation reaction in the kidney Once the 1-hydroxylase is bypassed by the administration of 1,25- OH)2D3, actinomycin D does not block the transport process in the rat at least This finding has been confirmed and extended " Tsai et al. have provided conflicting evidence in the chick that actinomycin D does block the intestinal response to 1,25-(OH)2D3 However, they found it necessary to administer the actinomycin D every 2 hr before a block could be effected. Whether this is a bona fide block or a toxic reaction to the antibiotic remains undetermined. In any case the use of RNA and protein synthesis inhibitors in vivo to deduce the mechanism of action of 1,25-(OH)2D3 results in unclear and difficult to interpret results, especially if RNA and protein synthesis is incompletely blocked ... 

The mitochondrial ribosomes of mammals are small (about 555) and insensitive to erythromycin and lincomycin, although these antibiotics penetrate freely into the mitochondria. These ribosomes are sensitive to chloramphenicol which, fortunately, does not normally penetrate into mammalian mitochondria. Chloroplasts have ribosomes that are sensitive to most of the protein synthesis inhibitors that injure bacteria (Kiintzel and Noll, 1967). 

Chlamydomonas reinhardi is sensitive to the protein synthesis inhibitor, erythromycin. At the time, some erythromycin-resistant strains had been isolated and described, and we were considering experimental approaches to locate the sites of structural genes for proteins of plastid ribosomes. It seemed reasonable to use erythromycin resistance as a genetic marker if we could be certain that the antibiotic interacts with some part of the chloroplast ribosome and was not lethal for some other reason. Erythromycin was known to bind to the large subunit of Escherichia coli ribosomes, and the alteration leading to resistance in the bacteria was found to reside in a single protein in the 50 S subunit. ... 

Resistance to tetracyclines. The tetracyclines Figure 7.3) are a family of closely related antibiotics now numbering at least seven, which are inhibitors of protein synthesis [150]. The tetracyclines are broad spectrum antibiotics, oxytetracycline being the most active against strains of Ps. aeruginosa. In sensitive strains, the range of minimum inhibitory concentrations (MIC values) is 10-30 /xg/ml. However, strains with MIC values of greater than lOp-g/ml are considered clinically resistant. 

Protein synthesis in mitochondria is dependent on the suppty of ATR either oxidative phosphorylation, or a steady supply of ATP must be provided. From a pharmacological standpoint, it is interesting that the incorporation of amino acids is affected by th3iroid hormone in vivo. The labelled amino acids are incorporated into an insoluble protein fraction present in the membrane and none of the soluble mitochondrial enzymes studied so far become labelled to any appreciable extent. The process of protein synthesis in mitochondria, as monitored by the incorporation of amino acids, displays some peculiar characteristics it is inhibited by a variety of other amino acids, possibly due to competitive effects among different amino acids for a common transport mechanism. Also peculiar is the sensitivity to chloramphenicol, and the insensitivity to cycloheximide, which is typical of bacterial systems, and not of microsomal systems. Then, there is the observation that actinomycin-D (a known inhibitor of the nuclear DNA-dependent RNA polymerase), inhibits protein synthesis in mitochondria after treatments have been applied which affect the permeability of the membrane, thus permitting penetration of the antibiotic. This last observation indicates synthesis of messenger RNA in mitochondria via a specific DNA-dependent RNA polymerase. Protdn synthesis in mitochondria is thus apparently dependent on the continuous synthesis of RNA this is possibly due to a peculiar lability of mitochondrial messenger RNA. 

In most systems in which either whole cells, protoplasts, or cell fractions are used, peptide and protein synthesis can be differentiated various amino acid analogues can selectively suppress the former whereas enzymes and antibiotics that specifically inhibit either DNA or RNA function or RNA or protein synthesis can selectively suppress the latter. In one cell-free system, however, peptide and protein synthesis cannot be differentiated in this system, formation of the peptide antibiotics require the same ingredients (and are sensitive to the same inhibitors) as those needed for (or antagonistic to) production of cell proteins. One of the essential ingredients consists of a messenger RNA molecule of 36 2 nucleotides. The reasons for the differences between systems in which differentiation can or cannot be achieved are presently unknown. 

Structural differences in mRNAs may cause not only different stabilities (half-lives) of mRNAs themselves, but may also cause a different affinity of mRNA to ribosomes. In the latter case, the mRNA to ribosomes affinity may result in a different stability of the initiation complex for protein synthesis, which possibly causes the different sensitivity to antibiotics known to be inhibitors of initiation of protein synthesis, such as kasugamycin. 

Rifampicin is also an inhibitor of the synthesis of a number of phages and viruses. It has been demonstrated that the RNA polymerase, which transcribes phage p 22 following infection of Bacillus subtilis, retains the rifampicin sensitivity of the host cell enzyme , Rifampicin also inhibits the formation of infectious vaccinia virus and viral particles. Whereas virion formation is completely inhibited neither the synthesis of RNA and protein nor the activity of in vitro RNA polymerase associated to the virion is affected lt>, Rifampicin inhibits the multiplication of poxvirus in vitro and in vivo. The side chain of this antibiotic derivative appears to be essential for the anti-viral effect and anti-trachomal activity found in... 

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