Wednesday, September 14, 2011

Mechanisms of Antibiotic Action

Antimicrobial substance is any substance of natural, semisynthetic, or synthetic origin that at in vivo concentrations kills or inhibits the growth of micro-organisms by interacting with a specific target (Cerf et al., 2010).

While antibiotics are natural antimicrobial agents produced by microorganisms such as fungi, actinomycetes and bacteria that is capable in small concentrations to kill or inhibit the growth of other bacteria. However, in common usage antibiotic means antibacterial agent, excluding agents with antiviral and antifungal activity (Bauman, 2009b).
It is hard to imagine hospital medicine in the preantibiotic era, indeed many of the great advances of modern medicine and surgery would not have been possible without the ability to rely on antibiotics to cure secondary infections (Mackenzie et al., 2007).
Mechanisms of antibiotic action:
Antibiotics target structures and pathways that are unique and important to bacteria such as cell wall synthesis, cytoplasmic membrane synthesis, protein synthesis, nucleic acid (DNA or RNA) synthesis and intermediary metabolism (McCallum, 2010).
A-Inhibition of cell wall synthesis:
Bacterial cell wall function and structure:
A cell wall maintains cellular integrity by countering the effects of osmosis when the cell is in a hypotonic solution. If the wall is disrupted, it no longer prevents the cell from bursting as water moves into the cell by osmosis (Dmitriev et al., 2005).
The major structural component of a bacterial cell wall is its peptidoglycan layer. Peptidoglycan is a huge macromolecule composed of polysaccharide chains of alternating N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) molecules that are cross linked by short peptide chains extending between NAM subunits. To enlarge or divide, a cell must synthesize more peptidoglycan by adding new NAG and NAM subunits to existing NAG-NAM chains, and the new NAM subunits must then be bonded to neighboring NAM subunits (Meroueh et al., 2006).
B-Inhibition of cytoplasmic membrane:
Beneath the cell wall, the cytoplasmic membrane essentially acts as a bag that contains the cytoplasm and controls the passage of chemicals into and out of the cell. Extensive damage to membranes' proteins or phospholipids allows the cellular contents to leak out and if not immediately repaired causes death (Manuselis and Mahon, 2007).
Polymyxin B, polymyxin E (colistin), amphotricin B, imidazoles, triazoles and polyenes exert their actions by altering the bacterial cell membranes. The inhibition of cell membrane function leads to escape of macromolecules from the cell resulting in cell damage or death (Chakraborty, 2009).
Polymyxin is effective against gram-negative bateria, particularly pseudomonas, but because it is toxic to human kidneys it is usually reserved for use against pathogens that are resistant to other antibacterial drugs (Bauman, 2009b).
Daptomycin is a new lipopeptide antibiotic that is rapidly bactericidal by binding to the cell membrane in a calcium dependent manner causing depolarization of bacterial membrane potential. This leads to intracellular potassium release. This agent has been approved for use in the treatment of Staphylococcus aureus blood stream infections and skin and soft tissue infections caused by gram-positive bacteria, particularly those organisms that are highly resistant to β-lactam agents and vancomycin (Brooks and Carroll, 2010).
C-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).

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