Protein Biosynthesis Inhibition

Protein biosynthesis involves the translation of the information contained in a base sequence in a specific mRNA into the synthesis of an amino acid sequence, or peptide. 

Both antibiotics possess moderate systemic activity. They may have activity against plants and animals. 

---

Table 3. Natural and Semi-synthetic Antibiotics of Protein Biosynthesis Inhibition...

Tamandarins A 11a and B11b Didemnid ascidian [33] In vitro antitumor activity in clonogenic assays (1—2ngml ) and protein biosynthesis inhibition properties [33] 1 oullie et al. [34]... 

Aminoglycosides Tetracyclines Chloramphenicol Erythromycin Clindamycin Spectinomycin Mupirodn Fusldfc add Inhibition of protein biosynthesis... 

Clindamycin, a lincosamide derivative, inhibits protein biosynthesis within a unique organelle of the parasite, termed apicoplast. Its mode of action is similar to that of spiramycin. 

GatCAB amidotransferase.This natural product mimics the charged 3 -terminus of aa-tRNA and has been used as a tool for the study of protein biosynthesis. The parent compound 22 is a very weak inhibitor of AdT. The amino acid chain is related to tyrosine and differs from the glutamic and aspartic side chains transformed in the kinase or the transamidase steps. Replacement of the methoxyphenyl moiety of puromycin by carboxylic acid derivatives (23-26) improved the ability to inhibit this AdT. Stable analogues of the transition state in the last step of the transamidation process (27-29) where the carbonyl to be attacked by NH3 is replaced by tetrahedral sulfur or phosphorus atom with a methyl group mimicking ammonia exhibited the highest activity. 

Many of the antibiotics used clinically are active by their ability to inhibit protein biosynthesis in bacteria. The individual steps of protein biosynthesis all seem susceptible to disruption by specific agents. Some specific examples are listed below ... 

Naturally, if such materials are going to be useful as antibiotic drugs, we require a selective action. We need to be able to inhibit protein biosynthesis in bacteria, whilst producing no untoward effects in man or animals. Although the mechanisms for protein biosynthesis are essentially the same in prokaryotes and eukaryotes, there are some subtle differences, e.g. in the nature of the ribosome and how the process is initiated. Without such differences, the agent would be toxic to man as well as to bacteria. 

As a group, the protein biosynthesis inhibitors comprise the second largest class of antibiotics available for clinical use. Natural product classes of antibiotics that inhibit the protein biosynthesis are aminoglycosides, tetracyclines, chloramphenicol, macrolides, lincosamides, fusidic acid, streptogramins and mupirocin (Fig. 7). 

Macrolides, lincosamides and streptogramins are protein biosynthesis inhibitors that bind to 50S subunit of the ribosome and inhibit peptidyl tRNA translocation from the A-site to the P-site." Macrolides have a glycosylated 14-, 15- or 16-membered lactone ring structure and are produced by several species of Streptomyces. Lincosamide antibiotics were isolated initially from Streptomyces lincolnensis but later isolated from different species of Streptomcyces. Streptogramins were also isolated from Streptomycesgraminofaciens and subsequently from several different Streptomyces species. There are two structurally different streptogramins, A and B they are bacteriostatic individually and can be bactericidal when combined. 

The covalent trapping of the enzyme leads to a depletion of the cellular pool of DNMTs and subsequent DNA hypomethylation. This in turn results in activation with respect to the reactivation of silenced genes. Additionally, the covalently trapped DNMT may inhibit RNA and DNA polymerases, which leads to an inhibition of protein biosynthesis and DNA strand breaks. This may lead to apoptosis and hence cytotoxicity. Thus, it is not easy to dissect the reasons for the clinical efficacy of these inhibitors in terms of real epigenetic and plain cytotoxic effects [81]. 

A well studied example for control at the level of eIF-2 is the regulation of protein biosynthesis in erythroid cells (review Chen and London, 1995). A decrease in the heme concentration in reticulocytes leads to inhibition of globin synthesis at the level... 

In certain situations, e.g., inhibition of protein biosynthesis, TNF receptor activation has a proapoptotic effect, however, in that caspases are activated and cell death is initiated. 

The NSAIDs (eg, indomethacin, ibuprofen see Chapter 36) block both prostaglandin and thromboxane formation by reversibly inhibiting COX activity. The traditional NSAIDs are not selective for COX-1 or COX-2. Selective COX-2 inhibitors, which were developed more recently, vary—as do the older drugs—in their degree of selectivity. Indeed, there is considerable variability between (and within) individuals in the selectivity attained by the same dose of the same NSAID. Aspirin is an irreversible COX inhibitor. In platelets, which are anuclear, COX-1 (the only isoform expressed in mature platelets) cannot be restored via protein biosynthesis, resulting in extended inhibition ofTXA2 biosynthesis. 

There are two commercial fungicides, the antibiotics blasticidin S and kasugamycin, that act via the inhibition of protein biosynthesis (Figure 4.19). Blasticidin S is a fermentation product obtained from cultures of Streptomyces griseochromogenes, and has specific activity in the control of P. oryzae, similar to kasugamycin, a secondary metabolite of S. kasugaensis. However, much of the earlier work on mode of action was carried out using another antibiotic, cycloheximide. 

Florfenicol targets the bacterial ribosome and inhibits bacterial protein biosynthesis. Acquired resistance has been reported, the forms being ribosomal mutations and reduction of the cell permeability. The molecular structure of florfenicol precludes the possibility that its toxicity is associated with idiosyncratic anemia. 

Macrolide antibiotics target the bacterial ribosome and inhibit the bacterial protein biosynthesis. Many gram-negative bacteria are inherently resistant to mac-rolides because their outer membrane is impermeable to macrolides. Several mechanisms of acquired resistance have been reported. In some cases, resistance is conferred by methylation of ribosomes by methylase enzymes, the genes of... 

Protein synthesis is a central function in cellular physiology and is the primary target of many naturally occurring antibiotics and toxins. Except as noted, these antibiotics inhibit protein synthesis in bacteria. The differences between bacterial and eukaryotic protein synthesis, though in some cases subtle, are sufficient that most of the compounds discussed below are relatively harmless to eukaryotic cells. Natural selection has favored the evolution of compounds that exploit minor differences in order to affect bacterial systems selectively, such that these biochemical weapons are synthesized by some microorganisms and are extremely toxic to others. Because nearly every step in protein synthesis can be specifically inhibited by one antibiotic or another, antibiotics have become valuable tools in the study of protein biosynthesis. 

Aminoglycosides. Antibiotics in the aminoglycoside group characteristically contain amino sugars and deoxystreptamine or streptamine, This family of antibiotics has frequently been referred to as aminocyclitol aminoglycosides. Representative members are streptomycin, neomycin, kanamycin, gentamicin, tobramycin, and amikacin. These antibiotics all inhibit protein biosynthesis,... 

Lincomycin. The lincomycins and celesticetins are a small family of antibiotics that have carbuliydrate-lype structures. Clindamycin, a chemical modification of lincomvcin, is clinically superior, Antibiotics in this family inhibit gram-positive aerobic and anaerobic bacteria by interfering with protein biosynthesis. 

ANTIBIOTICS ELFAMYCINS. The elfamyans are so named because they exhibit antimicrobial activity through the inhibition of protein biosynthesis via binding to the Wongation factor Tu. All of the known elfamyans are listed in Table 1. These antibiotics are distinguished by low mammalian toxicity, narrow-range antimicrobial activity, and positive effects on feed utilization and growth promotion in farm animals. Elfamyans also improve milk production in lactatmg ruminants. 

---