High-molecular-weight penicillin-binding proteins (HMW PBPs)

High-molecular-weight penicillin-binding proteins (HMW PBPs) are essential bacterial enzymes that catalyze the final stages of peptidoglycan assembly, the primary structural component of the bacterial cell wall (Sauvage et al., 2008). These proteins are typically divided into Class A PBPs, which are bifunctional enzymes possessing both transglycosylase and transpeptidase activities, and Class B PBPs, which function primarily as transpeptidases (Macheboeuf et al., 2006). By facilitating the cross-linking of glycan strands, HMW PBPs maintain the structural integrity and osmotic stability of the bacterial cell. They serve as the primary molecular targets for the beta-lactam class of antibiotics, including penicillins, cephalosporins, and carbapenems (Bush & Bradford, 2016). These drugs mimic the natural substrate of the PBPs and form a stable covalent bond with the enzyme's active site, effectively halting cell wall synthesis and leading to bacterial death. Resistance to these agents often involves structural modifications in the HMW PBPs that reduce their affinity for the drugs while maintaining their catalytic function (Zapun et al., 2008).

Other names

Other high-molecular-weight PBPsClass A PBPsClass B PBPsMultimodular PBPsPenicillin-binding protein 1aPenicillin-binding protein 1bPenicillin-binding protein 2Penicillin-binding protein 3Peptidoglycan glycosyltransferase/transpeptidase

Beta-lactam antibiotics act as structural analogs of the D-alanyl-D-alanine terminus of peptidoglycan precursors, covalently binding to the active-site serine of the transpeptidase domain of HMW PBPs. This irreversible acylation inhibits the cross-linking of peptidoglycan chains, leading to cell wall weakening, induction of the bacterial autolytic system, and eventual osmotic lysis.