Penicillin-binding protein 2, 3, and 4 (PBP2, PBP3, PBP4)

Penicillin-binding proteins (PBPs) are a family of membrane-associated enzymes essential for the biosynthesis and maintenance of the bacterial cell wall (Wikipedia, MDPI). Specifically, PBP2, PBP3, and PBP4 play distinct yet complementary roles in peptidoglycan assembly: PBP2 and PBP3 are high-molecular-weight transpeptidases primarily involved in cell elongation and septum formation during division, while PBP4 is a low-molecular-weight enzyme with carboxypeptidase or endopeptidase activity that modulates peptidoglycan cross-linking (NIH, RCSB). These proteins are the definitive targets for beta-lactam antibiotics, including penicillins, cephalosporins, and carbapenems (NIH, MDPI). These drugs act as substrate analogs that covalently bind to the active-site serine of PBPs, irreversibly inhibiting their ability to cross-link peptidoglycan chains (Wikipedia, NIH). This disruption leads to a loss of cell wall integrity, triggering bacterial lysis and death (NIH, Wikipedia). Clinical resistance frequently arises through mutations in these PBPs that decrease their affinity for antibiotics or through the acquisition of alternative PBPs, making them a focal point for the development of next-generation antimicrobial agents (MDPI, NIH).

Other names

DD-transpeptidaseDD-carboxypeptidaseDD-endopeptidasePeptidoglycan glycosyltransferasemrdAftsIdacBpbpApbpBpbpCpbpDpbp2pbp3pbp4

Beta-lactam antibiotics act as substrate analogs of the D-alanyl-D-alanine terminus of peptidoglycan precursors. They covalently bind to the active-site serine residue of PBPs, forming a stable acyl-enzyme intermediate that inhibits the transpeptidation (cross-linking) reaction, leading to cell wall instability and bacterial lysis (Wikipedia, NIH).