Bacterial penicillin-binding protein transpeptidase domain (PBP)

Bacterial penicillin-binding proteins (PBPs) are a group of essential enzymes involved in the final stages of peptidoglycan biosynthesis, which is the primary structural component of the bacterial cell wall [1]. The transpeptidase domain of these proteins is specifically responsible for catalyzing the cross-linking of glycan strands by forming peptide bonds between peptide side chains, providing the mechanical strength necessary to withstand internal osmotic pressure [2][4]. These domains are the primary targets for beta-lactam antibiotics, including penicillins, cephalosporins, and carbapenems. The drugs act as substrate mimetics that covalently acylate the active-site serine of the transpeptidase, thereby halting cell wall assembly and triggering bacterial autolysis [3]. Because peptidoglycan is absent in mammalian cells, PBPs represent highly selective targets for antibacterial therapy. However, the clinical effectiveness of targeting PBPs is increasingly threatened by the emergence of resistance, often mediated by the acquisition of alternative PBPs with low drug affinity or the production of beta-lactamase enzymes [1][5].

Other names

DD-transpeptidasePeptidoglycan transpeptidasePenicillin-binding proteinDD-peptidaseD-alanyl-D-alanine carboxypeptidaseBacterial penicillin-binding proteins – transpeptidase domains

Beta-lactam antibiotics function as structural analogs of the D-alanyl-D-alanine terminus of peptidoglycan precursors. They covalently bind to the active-site serine residue within the transpeptidase domain of PBPs, forming a stable acyl-enzyme intermediate. This irreversible inhibition prevents the cross-linking of peptidoglycan chains, which compromises the structural integrity of the bacterial cell wall and leads to osmotic lysis and cell death [1][3].