Penicillin-binding protein and beta-lactamase (PBP/BL)

Penicillin-binding proteins (PBPs) are essential bacterial enzymes, primarily transpeptidases, that catalyze the final cross-linking steps of peptidoglycan cell wall synthesis (Macheboeuf et al., 2013). They are the primary therapeutic targets for beta-lactam antibiotics, which mimic the D-alanyl-D-alanine substrate and form a stable covalent bond with the PBP active site, thereby halting cell wall assembly and causing bacterial death (StatPearls, 2023). Beta-lactamases are a diverse family of enzymes produced by bacteria that confer resistance by hydrolyzing the beta-lactam ring of antibiotics, rendering them inactive before they can reach their PBP targets (Bush & Bradford, 2016). Because beta-lactamases protect bacteria from PBP-targeting drugs, they are themselves targets for beta-lactamase inhibitors like clavulanic acid. This target group is central to the treatment of a wide range of bacterial infections, though its utility is increasingly challenged by the evolution of modified PBPs and novel beta-lactamase variants. Understanding the interplay between these two protein classes is vital for developing effective antimicrobial therapies and overcoming resistance mechanisms (NIH, 2022).

Other names

DD-peptidaseDD-transpeptidaseBeta-lactamasePenicillin-binding proteinPBPBLSerine hydrolase

Beta-lactam antibiotics act as pseudosubstrates for penicillin-binding proteins (PBPs), forming a stable acyl-enzyme intermediate that inhibits the transpeptidation step of peptidoglycan synthesis, leading to cell wall lysis (StatPearls, 2023). Beta-lactamase inhibitors function by binding to the active site of beta-lactamase enzymes, preventing the hydrolysis of the beta-lactam ring in co-administered antibiotics (Bush & Bradford, 2016).