Cell wall-active antibiotic

What does the bacterial cell wall provide

mechanical strength, maintains cell shape and protects the cell from osmotic lysis.

Why is it ideal that the cell wall is present in bacteria but not humans

it represents and ideal target for antimicrobial therapy and is the basis of selective toxicity.

how do antimicrobial drugs act

by interfering with cell wall biosynthesis most importantly the B-lactam antibiotics and the glycopeptides.

What is happening to the effectiveness of antimicrobial drugs

it is being increasingly compromised by the emergence of resistance including MRSA

what is the bacterial cell wall comped of

Peptidoglycan a polymer that surrounds the cytoplasmic membrane.

What does peptidoglycan consist of

Repeating disaccharide units of N-acetylglucosamine (NAG) and A-acetylmuramic acid (NAM)

What are NAG and NAM linked together by

B-1,4 glycosidic bonds

What is attached to each NAM residue

Short peptide side chain and cross-linking between these peptide chains provides the cell wall with its strength

steps of peptidoglycan synthesis

precursors are synthesised in the cytoplasm, transported across the cytoplasmic membrane, and then incorporated into the existing cell wall

Final stages of peptidoglycan synthesis

Transglycosylation and transpeptidation

transglycosylation

links the sugar backbone

transpeptidation

cross-links the peptide side chains

What are the later step of peptidoglycan synthesis catalysed by

enzymes known as penicillin-binding proteins.

What does inhbition of cell wall synthesis do

leads to cell lysis and death particularly in actively growing bacteria

what is the most important class of cell-wall active antimicrobail drugs

beta-lactam

Examples of beta-lactams

penicillins, cephalosporins, monobactams

What do all beta-lactams share in common

a beta-lactam ring structure which is critical for their antimicrobial activity

What do beta-lactams bind to

PBPs particularly those with transpeptidase activity

What does beta-lactam do by binding to these sites

inhibit the transpeptidation reaction needed for cross-linking peptidoglycan strands meaning the newly synthesised cell wall is weak and unable to withstand osmotic pressure which leads to cell death

when is the activity of beta-lactams the most pronounced

in actively dividing cells where wall synthesis is ongoing

Name a glycopeptide antibiotic

vancomycin

what does vancomycin bind to

D-alanine-D-alanine ends of the peptide side chains

What does the bindng of vancomycin do

blocks transglycosylation and transpepitidation preventing incorporation of new peptidoglycan subunits into the cell wall.

How is vancomycin different to beta-lactams

it does not bind to PBPs but physically prevents the enzymes involved in cell wall synthesis from accessing their substrate

What is vancomycin particulalry effective against

Gram-positive bacteria where the peptidoglycan layer is exposed but it is ineffective against gram-negative bacteria where there is a protective membrane

one mechanism bacteria have evolved to resist the action of cell wall-active antimicrobial drugs

enzymatic inactivation

what are beta-lactamases

β-lactamases cleave the β-lactam ring, preventing the antibiotic from functioning.

where can these enzymes be found

both Gram-positive and Gram-negative bacteria and can be encoded on chromosomes or plasmids, facilitating their spread

What is another resistance mechanisms

modification of the antibiotic target

What changes can be made to antibiotic target

changes in PBPs can reduce β-lactam binding but still allow cell wall synthesis.

what else can contibute to resistance

Reduced entry of the antibiotic can also cause resistance. In Gram-negative bacteria, changes in porin proteins can stop the antibiotic from entering the cell.