Mechanism of action of beta lactam antibiotics
(like penicillins and cephalosporins)
The beta-lactam antibiotics can destroy susceptible bacteria.
* The cell walls of bacteria are quiteessential for their normal growth and development.
* Peptidoglycan is a heteropolymeric component of cell wall which provides tough mechanical stability by virtue of its highly cross-linked lattice structure .
* In gm(+)microorganisms, the cell wall is 50 - 100 mothick, but it is only 1 (or) 2 molecules thick in gram(-)
* The peptidoglycan is composed of glyco chains, which are linear strands of 2 alternating amino sugars
(N-acetylglucosamine and N-acetylmuramic acid) which arecross-linked by
the peptide chains.(1)
*The biosynthesis of peptidoglycan involves for about 30 bacterial enzymes and may
be considered in 3 stages. The first
stage, i.e..,precursor formation, takes place in cytoplasm.
*The product of it, uridinediphosphate(UDP)-acetylmuramyl-pentapeptide, accumulates in the cells when subsequent synthetic stages are then inhibited. The last reaction in synthesis of this compound is addition of a dipeptide, and D-alanyl-D-alanine
.Synthesis of dipeptide involves a prior racemization of L-alanine andcondensation that is catalyzed by D-alanyl-D-alanine synthetase enzyme. D-Cycloserine is a
structural analogue of D-alanine and it acts as a competitive inhibitor of both racemase and the synthetase(1
* During the reactions of second stage,UDP-acetylmuramyl-pentapeptide and UDP-acetylglucosamine are linked with the release of the uridine nucleotides to form a long(1)polymer chain.
* The3rd and final stage involves the completion of a cross-link. This is then(1)accomplished by transpeptidation reaction that occurs outside cell membrane.
*The transpeptidase enzyme itself is membrane-bound.The last glycine residue of a pentaglycine bridge is linked to 4thresidue of the pentapeptide , releasing the 5th residue.
* It is this last step in the peptidoglycan synthesis that is inhibited by b-lactam antibiotics and glycopeptide antibiotics such as vancomycin(1)
* Stereomodels reveal that the conformation of penicillin is very identical to that of D-alanyl-D-alanine. The transpeptidase enzyme probably is acylated by penicillin antibiotic;i..e..,, penicilloyl enzyme apparently is formed, with the cleavage of 3/4 CO3/4N 3/4 bond of a(1)b-lactam ring.
* Even the inhibition of a transpeptidase enzyme just described is demonstrably important, there are additional, related targets for the actions of penicillins&cephalosporins; they arecollectively termed as penicillin-binding proteins. All bacteria(1)haveseveral such entities; for ex: Staphylococcusaureus has 4 PBPs,whereas E.coli has atleast seven PBP's.
* The Penicillin Binding Proteins vary in their affinities for different b-lactam antibiotics, although the interactions eventually become covalent bonded. The higher-molecular-weight PBPs of E. coli include the transpeptidases that are
responsible for synthesis of
Other PBPs in E. coli include
those that are necessary for the maintenance of the rodlike shape of bacterium and for septum formation at cell divisionprocess.
*Inhibition of transpeptidases causes spheroplast formation &rapid lysis.However inhibition of these activities of other PBPs may cause delayed lysis of(PBP 2) or the production of a long, filamentous forms of bacterium (PBP 3).
*The lethality of penicillin antibiotic for bacteria appears to be involved both lytic and nonlytic mechanisms.(2)
*Penicillin' disruption of balance between Penicillin Binding Proteins-mediated peptidoglycan assembly and murein
hydrolase activity results in process of autolysis process.(3)
*Nonlytic killing by penicillin antibiotic may involve holin-like proteins in the bacterial membrane which collapses the cell membrane potential.(3)
1. http://pharmacologycorner.com/penicillin-mechanism-of-action-videos-and- animations/ (accessed on 13-9-11 at 6:58 p.m)
13-9-11 at 6:58 p.m)
on 13-9-11 at 6:58 p.m)
on 13-9-11 at 6:58 p.m
5. http://microblog.me.uk/143 (accessed on 13-9-11 at 6:58 p.m)
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