Bacterial cell wall transpeptidase (PBP (Penicillin-binding protein))

Bacterial cell wall transpeptidases are enzymes that catalyze the cross-linking of peptide side chains in peptidoglycan, a critical process in the construction and maintenance of the bacterial cell wall. These enzymes are primarily classified as DD-transpeptidases, also known as penicillin-binding proteins (PBPs), and LD-transpeptidases, which together form peptide cross-links of various types (e.g., 4-3 between D-alanine and mDAP, 3-3, or 1-3). Inhibition of these enzymes disrupts cell wall integrity, leading to bacterial cell death, which is the mechanism of action for major antibiotic classes including penicillins and cephalosporins. The widespread clinical use of β-lactam antibiotics targets these enzymes, but bacterial resistance—especially through mutations in PBPs, acquisition of alternative transpeptidases, or β-lactamase production—presents ongoing therapeutic challenges. Transpeptidases are essential for bacterial survival and proliferation and remain focal points in the development and monitoring of antibacterial therapies.

Other names

Penicillin-binding protein (PBP)DD-transpeptidaseLD-transpeptidasePeptidoglycan transpeptidase

Irreversible inhibition of transpeptidase active site (e.g., β-lactam antibiotics mimic the D-Ala-D-Ala moiety and covalently bind to PBPs, blocking peptide cross-linking of peptidoglycan); Competitive inhibition (structural mimics that compete with the natural substrate); Bypassing inhibition (some drugs target LD-transpeptidases, which can evade classical β-lactam antibiotics)