Inhibitors of Gram-positive Cell Wall Synthesis

Bacterial cell walls are generally rigid and composed mainly of peptidoglycan.

Structurally, peptidoglycan consists of long glycan chains cross-linked by short peptides, which form a mesh that protects the cell against osmotic pressure.

Because peptidoglycan is essential for cell survival, beta-lactam antibiotics such as penicillin interfere with its synthesis in actively growing cells.

These antibiotics contain a distinctive four-membered beta-lactam ring.

This ring mimics the natural dipeptide D-alanyl-D-alanine, a substrate for the transpeptidase activity of penicillin-binding proteins, or PBPs.

These proteins are responsible for cross-linking glycan chains in the peptidoglycan matrix.

When the beta-lactam ring covalently binds to the active site of a PBP, it blocks the cross-linking reaction.

As a result, the bacterial cell wall remains weak and incomplete, making the cells highly vulnerable to osmotic lysis.

At the same time, autolytic enzymes such as murein hydrolases further contribute to the breakdown of the defective cell wall.