MECHANISMS OF ACTIONS OF ANTIMICROBIALS (A)

1. INHIBITION OF CELL WALL SYNTHESIS:

(A) Inhibition of Transpeptidation:

The biosynthesis of peptidoglycan involves about 30 bacterial enzymes. This is completed in three stages. First and second stage synthesis reactions take place in the cytoplasm that means inside the cytoplasmic membrane. Third stage is accomplished by transpeptidation and it occurs outside the cytoplasmic membrane. The peptidoglycan layer of the cell wall consists of polysaccharides and polypeptides. The polysaccharide regularly contains the amino sugars i.e. N-acetyl glucosamine (G) and N-acetyl Muramic acid (M). To amino sugars are attached short pentapeptide chains. The final rigidity of the cell wall is imparted by cross linkage of peptide chain. In cross-linking, terminal Glycine residue of the Pentaglycine Bridge is linked to the 4^th residue of pentapeptide (D-Alanine) releasing the 5^th residue (D-Alanine). The cross linking is accomplished by transpeptidation reactions catalyzed by several enzymes. Small segments of two polymer chains and their amino acid side chains are shown below. These linear polymers must be cross linked by transpeptidation of side chains at points indicated in the figure in order to achieve the strength for cell viability.

All Penicillins, Cephalosporins, Carbapenems, and Monobactams (collectively they are known as B-lactam antibiotics) are selective inhibitor of bacterial cell wall synthesis. To do so drug binds to bacterial cells receptors called penicillin-binding proteins (PBP). The number of PBP’s in many bacteria is 3-6. Different receptors may possess different affinity for a drug and each PBP may mediate different mode of action for example binding of penicillin to one PBP may result in abnormal elongation of bacterial cell whereas attachment to other may cause defect in cell wall at the periphery leading to death of cell wall. After binding of B-lactam to PBP, the transpeptidation reaction is inhibited and synthesis of peptidoglycan is blocked. After the inhibition of synthesis of peptidoglycan, either removal or inactivation of an inhibitor of autolytic enzymes (autolysins or murein hydrolases) in the cell wall takes place. This results in activation of lytic enzymes and leads to the death of microbes.