Mechanism of action of BETALACTAM ANTIBIOTICS......

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Mechanism of action of beta lactam antibiotics

(like penicillins and cephalosporins)

The beta-lactam antibiotics can destroy susceptible bacteria.

(1)

* 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(-)
bacteria (1)

* 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

(2) peptidoglycan.

Diagram-1(4)

peptidogylcan

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)


Diagram-2(5)

mechanism of action

References:



1. http://pharmacologycorner.com/penicillin-mechanism-of-action-videos-and- animations/ (accessed on 13-9-11 at 6:58 p.m)

2. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC219812/(accessedon
13-9-11 at 6:58 p.m)

3. http://www.annualreviews.org/doi/abs/10.1146/annurev.bi.52.070183.004141(accessed
on 13-9-11 at 6:58 p.m)

4. http://www.biochem.arizona.edu/classes/bioc462/462bh2011/462bhonorsproje...(accessed
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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Comments

nishant upadhyay's picture

mam i am b.pharma student my prof. say every antibiotic synthesis from bacteria it is right or wrong??????????

upadhyay

Sandhya Sravya malla's picture

first of all upload your picture as a part of recognising you on this platform. and coming to your query....its not like every antibiotic is synthesized only from bacteria,some may be of fungal origin too like penicillin.... m.sandhyasravya@gmail.com pharma warriors
Satyajeeth Pandey's picture

Hi dear Good to see you guiding other new comers of this platform. good job

Satyajit Panda Asst. professor Maharajah's College Of Pharmacy