Notes on Bacterial Cell Wall Synthesis Interference

Other Agents That Interfere with Bacterial Cell Wall Synthesis

Peptidoglycan Synthesis

  • Peptidoglycan: A crucial component of the bacterial cell wall involved in cell wall growth and cross-linking.
  • Process Overview: The growing cell wall involves transglycosidation.
  • Key Components & Processes:
    • NAG (N-acetylglucosamine)
    • NAM (N-acetylmuramic acid)
    • Amino acids: L-Ala, D-Glu, L-Lys, D-Ala
    • D-Ala-D-Ala
    • Carrier lipid

Cycloserine

  • Source: Streptomyces garyphalus
  • Mechanism:
    • Mimics D-alanine.
    • Inhibits L-alanine racemase and D-Ala-D-Ala ligase.
  • Spectrum: Broad spectrum.
Cycloserine and D-Alanine Similarity
  • Cycloserine has a similar structure to D-Alanine, allowing it to interfere with enzymes that utilize D-Alanine.

Cycloserine Mode of Action

  • NAM is linked to three amino acids: Ala, Glu, Lys.
  • Then linked to the dipeptide D-Ala-D-Ala (obtained from L-Ala racemase).
  • NAM with pentapeptide chain is linked to C55 carrier lipid.
  • Addition of NAG and pentaglycyl chain.
  • Transglycosidase links disaccharide to the growing cell wall.
Application of Cycloserine
  • Used against Mycobacterium tuberculosis.
  • Acts as a partial agonist of the NMDA receptor in the brain.

Vancomycin

Vancomycin Structure
  • Complex molecule with:
    • Heptapeptide backbone
    • L-Lys-D-Ala-D-Ala 'tail'
Vancomycin Mode of Action
  • Fixed conformation of heptapeptide.
  • Attaches to the terminal L-Lys-D-Ala-D-Ala tail.
  • Dimerization possible.
  • Inhibits transglycosidase.
Vancomycin and Peptidoglycan Synthesis
  • NAM is linked to three amino acids Ala, Glu, Lys.
  • Then linked to dipeptide D-Ala-D-Ala (obtained from L-Ala racemase).
  • NAM with pentapeptide chain linked to C55 carrier lipid.
  • Addition of NAG and pentaglycyl chain.
  • Transglycosidase links disaccharide to growing cell wall.
Application of Vancomycin
  • Active against Gram-positive bacteria, e.g., MRSA (Methicillin-resistant Staphylococcus aureus).
  • Active against C. diff (Clostridioides difficile).
  • Inactive against Gram-negative bacteria.

Summary

  • Vancomycin targets transglycosidation prior to cross-linking.
  • Vancomycin is used to treat MRSA.
  • Cycloserine targets the initial stages of peptidoglycan formation.
  • Cycloserine mimics D-alanine and interferes with racemization and ligation processes.

Next week

  • Bacterial protein biosynthesis
  • Drugs that inhibit the ribosomal subunits of the 70S bacterial ribosome

Reading

  • An Introduction to Medicinal Chemistry, 6th Ed
  • Graham L Patrick
  • Chapter 19