Penicillin-binding protein (PBP-1A, PBP-1B, PBP-2, and PBP-3) (PBP)

Penicillin-binding proteins (PBPs) are a group of essential enzymes located in the periplasmic space of Gram-negative bacteria, where they catalyze the final stages of peptidoglycan biosynthesis [9, 11]. These proteins are categorized into high-molecular-weight (HMW) and low-molecular-weight (LMW) classes, with HMW PBPs like PBP-1A, PBP-1B, PBP-2, and PBP-3 serving as the primary lethal targets for beta-lactam antibiotics [11, 15]. PBP-1A and PBP-1B are bifunctional enzymes possessing both transglycosylase and transpeptidase activities, crucial for maintaining cell wall integrity and longitudinal growth [10, 11]. PBP-2 and PBP-3 are monofunctional transpeptidases specialized in cell elongation and septum formation during division, respectively [4, 17]. Beta-lactam antibiotics, including penicillins, cephalosporins, and carbapenems, act by covalently binding to the active-site serine of the transpeptidase domain, thereby inhibiting the cross-linking of peptidoglycan strands [5, 9]. This inhibition leads to characteristic morphological changes—such as filamentation from PBP-3 inhibition or spheroplast formation from PBP-2 inhibition—and ultimately results in bacterial cell lysis and death [4, 8, 17]. PBPs are central to the treatment of various bacterial infections, though their efficacy is increasingly challenged by resistance mechanisms such as the production of beta-lactamases and structural alterations in the PBPs themselves [5, 17].

Other names

Penicillin-binding proteinsDD-transpeptidasesPeptidoglycan glycosyltransferasesMurein polymerasesFtsIMrdAPonAPonBPenicillin-binding protein 1APenicillin-binding protein 1BPenicillin-binding protein 2Penicillin-binding protein 3

Covalent inhibition of the transpeptidase domain through acylation of the active-site serine residue, preventing peptidoglycan cross-linking and leading to cell wall instability and lysis.