Penicillin-binding protein - high-molecular-weight transpeptidase (HMW PBP) (HMW PBP)

High-molecular-weight (HMW) penicillin-binding proteins (PBPs) are essential bacterial enzymes located on the outer surface of the cytoplasmic membrane, where they catalyze the final stages of peptidoglycan synthesis (StatPearls, 2023). These enzymes are divided into Class A (bifunctional transglycosylases/transpeptidases) and Class B (monofunctional transpeptidases) and are responsible for cross-linking glycan strands to provide structural integrity to the bacterial cell wall (Sauvage et al., 2008). Because peptidoglycan is unique to bacteria, HMW PBPs are the primary targets for beta-lactam antibiotics, including penicillins, cephalosporins, and carbapenems (UniProt, 2024). These drugs act as substrate analogs that covalently bind to the active-site serine, irreversibly inhibiting the transpeptidase activity and leading to bacterial cell lysis (Macheboeuf et al., 2006). Resistance to these agents often occurs through the acquisition of low-affinity PBPs, such as PBP2a in methicillin-resistant Staphylococcus aureus (MRSA), or through mutations in the PBP active site (StatPearls, 2023).

Other names

DD-transpeptidasePeptidoglycan transpeptidasePBPPenicillin-binding proteinPBP1aPBP1bPBP2PBP3

Beta-lactam antibiotics function as structural analogs of the D-alanyl-D-alanine terminus of peptidoglycan precursors; they form a stable, covalent acyl-enzyme intermediate with the active-site serine of HMW PBPs, thereby blocking the transpeptidation reaction required for cell wall cross-linking (Macheboeuf et al., 2006; StatPearls, 2023).