Penicillin-binding protein 1-4 (PBP1-4) (PBP1-4)

Penicillin-binding proteins (PBPs) are a group of membrane-associated bacterial enzymes that play a critical role in the final stages of peptidoglycan cell wall assembly [1.2.1, 1.3.2]. They are classified into high-molecular-weight (HMW) and low-molecular-weight (LMW) proteins, with HMW PBPs being further divided into Class A (bifunctional transglycosylases/transpeptidases) and Class B (monofunctional transpeptidases) [1.3.2, 1.4.2]. These enzymes are essential for cell wall cross-linking and cell division, providing the structural rigidity necessary for bacterial survival [1.3.1, 1.3.4]. PBPs are the primary targets of beta-lactam antibiotics, such as penicillins, cephalosporins, and carbapenems, which act as structural analogs of the D-Ala-D-Ala peptide substrate [1.2.3, 1.3.1]. These drugs covalently bind to the active-site serine of the transpeptidase domain, irreversibly inhibiting the enzyme and leading to cell wall defects, osmotic lysis, and bacterial death [1.2.1, 1.2.4]. Resistance to these agents is a major clinical challenge, often mediated by the production of beta-lactamases or the acquisition of modified PBPs with reduced antibiotic affinity, such as PBP2a in methicillin-resistant Staphylococcus aureus (MRSA) [1.2.2, 1.4.3].

Other names

DD-transpeptidaseDD-carboxypeptidasePeptidoglycan transpeptidasePenicillin-binding protein 1Penicillin-binding protein 2Penicillin-binding protein 3Penicillin-binding protein 4

Beta-lactam antibiotics act as structural analogs of the D-alanyl-D-alanine terminus of the peptidoglycan precursor. They covalently bind to the active-site serine residue of the PBP transpeptidase domain, forming a stable acyl-enzyme intermediate that irreversibly inhibits the enzyme's ability to cross-link peptidoglycan strands, leading to cell wall instability and bacterial lysis [1.2.1, 1.2.3, 1.3.1].