scholarly journals Mechanism of action of a microsomal inhibitor of protein synthesis potentiated by oxidized glutathione

1973 ◽  
Vol 136 (2) ◽  
pp. 335-342 ◽  
Author(s):  
H. T. R. Rupniak ◽  
R. V. Quincey
Keyword(s):  
Protein Synthesis ◽  
Mechanism Of Action ◽  
Nucleoside Triphosphate ◽  
Oxidized Glutathione ◽  
Direct Inhibition ◽  
Nucleoside Triphosphate Diphosphohydrolase ◽  
Inhibition Of Protein Synthesis ◽  
Inhibitor Of Protein Synthesis

Extracts of microsomal fractions cause an inhibition of protein synthesis that is most pronounced in the presence of 0.1mm-GSSG and 0.01mm-GTP, and is abolished by thiol or 0.4mm-GTP (Scornik et al., 1967). Fractionation of microsomal extracts showed that this inhibition of protein synthesis was caused by an enzyme, nucleoside diphosphate phosphohydrolase. Direct inhibition of protein synthesis on detergent-treated polyribosomes by 0.1mm-GSSG was observed under conditions of GTP limitation induced by omission of a GTP-regenerating system, or addition of a nucleoside triphosphate diphosphohydrolase. Thus GSSG potentiated the inhibition of protein synthesis caused by an enzyme that promoted removal of GTP. The inhibition was abolished by adding 4mm-2-mercaptoethanol or 0.4mm-GTP. Nucleoside diphosphate phosphohydrolase was thought also to act by promoting removal of GTP, thus causing an inhibition of protein synthesis that was potentiated by GSSG.

scholarly journals Investigations of the Mode of Action and Resistance Development of Cadazolid, a New Antibiotic for Treatment of Clostridium difficile Infections

2013 ◽  
Vol 58 (2) ◽  
pp. 901-908 ◽  
Author(s):  
Hans H. Locher ◽  
Patrick Caspers ◽  
Thierry Bruyère ◽  
Susanne Schroeder ◽  
Philippe Pfaff ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Clostridium Difficile ◽  
Dna Synthesis ◽  
Mode Of Action ◽  
Cross Resistance ◽  
Resistance Development ◽  
Content Type ◽  
Inhibition Of Protein Synthesis ◽  
Inhibitor Of Protein Synthesis ◽  
Inhibition Of Dna Synthesis

ABSTRACTCadazolid is a new oxazolidinone-type antibiotic currently in clinical development for the treatment ofClostridium difficile-associated diarrhea. Here, we report investigations on the mode of action and the propensity for spontaneous resistance development inC. difficilestrains. Macromolecular labeling experiments indicated that cadazolid acts as a potent inhibitor of protein synthesis, while inhibition of DNA synthesis was also observed, albeit only at substantially higher concentrations of the drug. Strong inhibition of protein synthesis was also obtained in strains resistant to linezolid, in agreement with low MICs against such strains. Inhibition of protein synthesis was confirmed in coupled transcription/translation assays using extracts from differentC. difficilestrains, including strains resistant to linezolid, while inhibitory effects in DNA topoisomerase assays were weak or not detectable under the assay conditions. Spontaneous resistance frequencies of cadazolid were low in all strains tested (generally <10−10at 2× to 4× the MIC), and in multiple-passage experiments (up to 13 passages) MICs did not significantly increase. Furthermore, no cross-resistance was observed, as cadazolid retained potent activity against strains resistant or nonsusceptible to linezolid, fluoroquinolones, and the new antibiotic fidaxomicin. In conclusion, the data presented here indicate that cadazolid acts primarily by inhibition of protein synthesis, with weak inhibition of DNA synthesis as a potential second mode of action, and suggest a low potential for spontaneous resistance development.

THE EFFECT OF ACTINOBOLIN ON NUCLEIC ACID AND PROTEIN SYNTHESIS IN ESCHERICHIA COLI

1966 ◽  
Vol 12 (3) ◽  
pp. 515-520 ◽  
Author(s):  
D. E. Hunt ◽  
R. F. Pittillo ◽  
E. P. Johnson ◽  
F. C. Moncrief
Keyword(s):  
Escherichia Coli ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Nucleic Acid ◽  
Mechanism Of Action ◽  
Rna Synthesis ◽  
The Other ◽  
Cross Resistance ◽  
Inhibition Of Protein Synthesis

Actinobolin inhibits protein synthesis in Escherichia coli. When the antibiotic is added to a culture at the time of inoculation, RNA synthesis is also inhibited. Inhibition of RNA synthesis appears to be a consequence of inhibition of protein synthesis. Cross-resistance experiments suggest that the mechanism of action of actinobolin differs from that of the other inhibitors of protein synthesis, chloramphenicol and sparsomycin. Phenylalanine prevents the action of actinobolin provided the amino acid and antibiotic are added simultaneously; this effect is not observed if the phenylalanine is added 1 hour after the addition of the antibiotic. Evidence is presented that the mechanism by which phenylalanine prevents inhibition by actinobolin differs from that which has been suggested for azaserine and p-fluorophenylalanine.

scholarly journals Effects of inhibition of protein synthesis by cycloheximide on lipogenesis in mammary gland and liver of lactating rats

1982 ◽  
Vol 204 (2) ◽  
pp. 417-423 ◽  
Author(s):  
A F C Roberts ◽  
J R Viña ◽  
M R Munday ◽  
R Farrell ◽  
D H Williamson
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Mammary Gland ◽  
Liver Glycogen ◽  
Glycolytic Flux ◽  
Hepatic Lipogenesis ◽  
Plasma Insulin Concentration ◽  
Inhibition Of Protein Synthesis ◽  
Inhibitor Of Protein Synthesis

1. Administration of cycloheximide (an inhibitor of protein synthesis) to lactating rats raised the concentrations of amino acids, and in particular, the branched-chain amino acids (valine, leucine and isoleucine) in blood, liver and mammary gland. 2. Inhibition of protein synthesis increased the incorporation in vivo of L-[U-14C]leucine into lipids of mammary gland and liver. 3. Cycloheximide treatment caused no immediate change in the overall rate of lipogenesis in vivo (measured with 3H2O) in mammary gland but increased the rate in liver 3-fold; this latter effect also occurred in livers of virgin rats. 4. The increased rate of hepatic lipogenesis was not accompanied by significant changes in the plasma insulin concentration or the activity of acetyl-CoA carboxylase. 5. Although cycloheximide decreased the entry of total triacylglycerol into the circulation it did not alter the rate of secretion of newly synthesized saponifiable lipid. 6. Cycloheximide slightly stimulated lipogenesis from endogenous substrates in isolated hepatocytes, but this effect was abolished when lactate was the exogenous substrate. 7. Administration of cycloheximide to virgin rats decreased liver glycogen and increased the hepatic content of glucose 6-phosphate, pyruvate and lactate. 8. It is concluded that (a) there is no short-term link between the rate of protein synthesis and lipogenesis in the lactating mammary gland and (b) the increased rate of hepatic lipogenesis in cycloheximide-treated rats is mainly due to stimulation of glycogenolysis, glycolytic flux and consequent increased availability of pyruvate.

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