SAR and Mechanism of Action of Cephalosporins

Structure-Activity Relationship (SAR) of Cephalosporins:

1. Beta-Lactam Ring (Essential for Activity):

   • The beta-lactam ring is crucial for antibacterial activity. It is responsible for binding to penicillin-binding proteins (PBPs) and inhibiting cell wall synthesis. Any modifications to this ring often lead to loss of activity.

2. Dihydrothiazine Ring (Position 6 Modifications):

   • The dihydrothiazine ring fused to the beta-lactam ring provides stability and resistance to beta-lactamases. Modifications at position 7 of this ring impact the spectrum of activity.
     • E.g., Substitutions at position 7 can increase activity against Gram-negative bacteria by enhancing resistance to beta-lactamases.

3. Acyl Side Chain (Position 3 Modifications):

   • The acyl group at position 3 plays a role in determining the pharmacokinetic properties (absorption, distribution, metabolism, and excretion).
   • Modifications at position 3 can influence:
     • Resistance to beta-lactamases (e.g., adding bulky groups can protect the beta-lactam ring from enzymatic degradation).
     • Antibacterial spectrum (adjustments can make the drug more effective against Gram-positive or Gram-negative bacteria).

4. Methoxy Group at Position 7:

   • The addition of a methoxy group at position 7 (found in cephamycins, a subclass of cephalosporins) provides increased stability against beta-lactamase enzymes, particularly in Gram-negative bacteria.

5. Oxime Group at Position 7 (Cephalosporinase Resistance):

   • The oxime moiety attached to the acyl group at position 7 provides resistance to cephalosporinases, increasing activity against resistant organisms.

6. Quaternary Ammonium Group:

   • Some cephalosporins have a quaternary ammonium group at the 3-position, which increases their activity against Pseudomonas aeruginosa.

Mechanism of Action of Cephalosporins:

Cephalosporins, like other beta-lactam antibiotics, inhibit bacterial cell wall synthesis. The mechanism is as follows:

1. Inhibition of Penicillin-Binding Proteins (PBPs):

   • Cephalosporins target PBPs, which are enzymes responsible for the synthesis of the bacterial cell wall. PBPs catalyze the cross-linking of peptidoglycan chains, a crucial step in cell wall formation.

2. Blocking Peptidoglycan Cross-Linking:

   • Cephalosporins bind to PBPs and block the transpeptidation reaction that links the peptidoglycan strands, leading to the inhibition of cell wall synthesis.

3. Disruption of Cell Wall Integrity:

   • As peptidoglycan cross-linking is inhibited, the bacterial cell wall becomes weak and unable to maintain its structure. This is particularly important during cell growth and division.

4. Bacterial Cell Lysis:

   • The inability to synthesize an intact cell wall leads to cell lysis and death, especially in actively dividing bacteria, due to osmotic pressure differences that the cell can no longer withstand.

Spectrum of Activity:

• First-generation cephalosporins are primarily effective against Gram-positive bacteria.
• Second-generation cephalosporins have enhanced activity against Gram-negative bacteria.
• Third-generation cephalosporins have further increased activity against Gram-negative bacteria, including some resistant strains.
• Fourth-generation cephalosporins have a broad spectrum of activity, covering both Gram-positive and Gram-negative bacteria, including Pseudomonas aeruginosa.
• Fifth-generation cephalosporins are effective against MRSA and multi-drug resistant bacteria.

This combination of structural modifications and the inhibition of bacterial cell wall synthesis makes cephalosporins a versatile class of antibiotics with a broad range of applications.