1. DENS 521 Clinical Dental Therapeutics
2nd Lecture By Abdelkader Ashour, Ph.D. Phone:

2. Beta-Lactam Antibiotics, Overview
Large group including:
Penicillins
Cephalosporins
Monobactams
Carbapenems
Bactericidal
Interfere with cell wall biosynthesis (by inhibiting cross-linking of peptidoglycans)
Most penicillins are destroyed by b-lactamase
Cephalosporins, carbapenems and monobactams all are relatively b-lactamase resistant
Wide usage
Penicillins are often first choice for fighting infections (cephalosporins second)
Resistance is becoming an increasing problem (see later)

3. Bacterial Cell Envelope

4. Mechanism of Action of b-Lactams
All b-lactam antibiotics, including penicillins, kill susceptible bacteria by specifically inhibiting the transpeptidase that catalyzes the final step in cell wall biosynthesis, the cross-linking of peptidoglycan
The cell wall is a rigid outer layer that is not found in animal cells:
It completely surrounds the cytoplasmic membrane, maintaining the shape of the cell and preventing cell lysis from high osmotic pressure
It is composed of:
Outer membrane, a lipid bilayer, is present in gram-negative but not gram-positive organisms. It is penetrated by porins, proteins that form channels providing hydrophilic access to the cytoplasmic membrane
A complex cross-linked polymer, peptidoglycan, consisting of polysaccharides and polypeptides
The polysaccharide contains alternating amino sugars, N-acetylglucosamine (G) and N-acetylmuramic acid (M)
A five-amino-acid peptide is linked to the N-acetylmuramic acid sugar. This peptide terminates in D-alanyl-D-alanine
Penicillin-binding proteins (PBPs) catalyze the transpeptidase reaction that removes the terminal alanine to form a crosslink with a nearby peptide, which gives cell wall its structural rigidity
b-Lactam antibiotics are structural analogs of the natural D-Ala-D-Ala substrate and they are covalently bound by PBPs at the active site

6. The transpeptidation reaction in that is inhibited by b-lactam antibioticsΘ

7. Inhibition of bacterial cell wall synthesis, MOA of Vancomycin vs b-Lactams

8. Mechanism of Action, In motion

9. Mechanism of Action of b-Lactams, so what!!
After a b–lactam antibiotic attaches to the PBP, the transpeptidation reaction is inhibited and peptidoglycan synthesis is blocked. Because of the cell wall defects, the bacteria swell and burst
The final bactericidal event is the inactivation of an inhibitor of the autolytic enzymes in the cell wall  this leads to lysis of the bacterium
NB: b-Lactams exert a bactericidal action on growing or multiplying germs