DENS 521Clinical Dental Therapeutics

2nd Lecture

By

Abdelkader Ashour, Ph.D. Phone: 4677212 Email: aeashour@ksu.edu.sa

Beta-Lactam Antibiotics, Overview

Bactericidal Interfere with cell wall biosynthesis (by inhibiting

cross-linking of peptidoglycans)

Large group including: Penicillins Cephalosporins Monobactams Carbapenems

Most penicillins are destroyed by -lactamase Cephalosporins, carbapenems and

monobactams all are relatively -lactamase resistant

Wide usage Penicillins are often first choice for fighting

infections (cephalosporins second)

Resistance is becoming an increasing problem (see later)

Bacterial Cell Envelope

Mechanism of Action of -Lactams All -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:

I. 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

II. 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

-Lactam antibiotics are structural analogs of the natural D-Ala-D-Ala substrate and they are covalently bound by PBPs at the active site

The transpeptidation reaction in that is

inhibited by -lactam antibiotics

-Lactam antibioticsΘ

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

Mechanism of Action, In motion

Mechanism of Action of -Lactams, so what!!

After a –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: -Lactams exert a bactericidal action on growing or multiplying germs