Wednesday, October 12, 2011

Antibiotics action:Inhibition of protein synthesis

Cells use proteins for structure and regulation, as enzymes in metabolism and as channels and pumps to move materials across cell membranes. Thus, a consistent supply of proteins is vital for the active life of a cell (Bauman, 2009a).
Many antimicrobial agents take the advantage of the differences between prokaryotic ribosomes (70S) and the eukaryotic ribosomes (80S) to selectively target bacterial protein translation without significantly affecting eukaryotes (Franceschi and Duffy, 2006).
The 70S ribosome is composed of two subunits 30S and 50S built with RNA and proteins (30S composed of 16S rRNA and ribosomal proteins, 50S subunit composed of 23S rRNA, 5S rRNA and ribosomal proteins) which assemble to produce a functional structure for protein synthesis. Each part undertakes a specific function. The small subunit 30S decodes mRNA. In the large 50S part, the protein is formed by the polymerization of amino acids according to the genetic code. tRNA molecules carry the amino acids. Ribosomes possess three tRNA binding sites A, P, and E, hosting the aminoacyl-tRNA, the peptidyl-tRNA, and the exiting tRNA, respectively. Each elongation cycle involves the advancement of the mRNA together with A→ P → E site passage of the tRNA molecule (Agmon et al., 2004).
Antibiotics that target the 30S ribosomal subunit:
• Aminoglycosides:
The aminoglycosides antibiotics (streptomycin, gentamycin, tobramycin, spectinomycin, kanamycin, neomycin and paromycin) are closely related drugs. They have action against a wide range of micro-organisms (Chakraborty, 2009).
The mode of action of streptomycin has been studied more intensively than other aminoglycosides, but all probably act similarly. The first step is the attachment of the aminoglycoside to a specific receptor protein (S12 in the case of streptomycin) on the 30S subunit of the microbial ribosome. Second, the aminoglycoside blocks the normal activity of the "initiation complex" of peptide formation (mRNA + formyl methionine + tRNA). Third, the mRNA message is misread on the "recognition region" of the ribosome; consequently, the wrong amino acid is inserted into the peptide, resulting in a non functional protein. Fourth, aminoglycoside attachment results in break up of polysomes and their separation into monosomes incapable of protein synthesis (Brooks and Carroll, 2010).
• Tetracyclines:
Tetracyclins bind to the 30S ribosomal subunit and inhibit protein synthesis by blocking the attachment of incoming aminoacyl-tRNA. Thus they prevent introduction of new amino acids to the growing peptide chain (Chopra and Roberts, 2001).
Antibiotics that target the 50S ribosomal subunit:
• Chloramphenicol:
The molecular target for chloramphenicol is the peptidyl transferase enzyme that links amino acids in the growing peptide chain. The effect of the antibiotic is thus to freeze the process of chain elongation, bringing bacterial growth to an abrupt halt. The process is completely reversible, and chloramphenicol is fundamentally a bacteriostatic agent (Biswas et al., 2008).
• Macrolides, Lincosamide and streptogramins :
Macrolides, lincosamides, and streptogramin B (MLSB) antibiotics are structurally dissimilar, but are grouped together due to a common mechanism of action. Macrolides include the drugs erythromycin, clarithromycin, and azithromycin. Clindamycin is the main lincosamide used clinically. Quinupristin, combined with streptogramin A dalfopristin, is the most commonly used streptogramin B antibiotic (Champney and Tober, 2000).
The binding site of these drugs is the 23S of bacterial ribosomal RNA. Binding of the antibiotic prevents movement of the ribosome from one codon to the next; as a result, translation is frozen and protein synthesis is halted (Tsui et al., 2004).
• Oxazolidinones:
The oxazolidinones are a relatively new class of antibiotics. These antibiotics inhibit bacterial growth by interfering with the 50S particle assembly and the binding of aminoacyl-tRNA to the ribosomal A site, as shown for linezolid (Leach et al., 2007).
Illustrates ribosomal structure. Action of macrolides on the peptidyl-tRNA molecule during elongation, resulting in inhibition of protein synthesis (Biswas et al., 2008

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