Penicillin-binding protein transpeptidase domain (PBP-TP)

Penicillin-binding proteins (PBPs) are a group of bacterial enzymes essential for the synthesis and remodeling of the peptidoglycan layer, which provides structural integrity to the bacterial cell wall [1, 2]. The transpeptidase domain of these proteins specifically catalyzes the cross-linking of glycan strands by forming peptide bonds between peptide side chains, a critical step for maintaining osmotic stability [2, 5]. This domain is the primary therapeutic target for beta-lactam antibiotics, such as penicillins, cephalosporins, and carbapenems [3, 10]. These drugs act as substrate analogs that covalently bind to a conserved catalytic serine residue in the transpeptidase active site, irreversibly inhibiting its activity [2, 8]. This inhibition leads to the accumulation of cell wall precursors and triggers autolytic enzymes, ultimately resulting in bacterial cell lysis and death [1, 5]. PBPs are critical targets for treating a wide range of bacterial infections, although resistance mechanisms like the acquisition of low-affinity PBPs (e.g., PBP2a in MRSA) or mutations in the transpeptidase domain pose significant clinical challenges [6, 12].

Other names

DD-transpeptidasePeptidoglycan transpeptidasePenicillin-binding domainD-alanyl-D-alanine transpeptidasePBP transpeptidase domain

Irreversible inhibition of the transpeptidase active site by mimicking the D-alanyl-D-alanine moiety of the peptidoglycan precursor, forming a stable covalent acyl-enzyme intermediate with the catalytic serine residue, which prevents the cross-linking of peptidoglycan chains and leads to bacterial cell lysis.