Penicillin-binding proteins (PBP1, PBP2, PBP4) (PBPs)

Penicillin-binding proteins (PBPs) are a family of essential bacterial enzymes, including PBP1, PBP2, and PBP4, that are critical for the biosynthesis and remodeling of peptidoglycan, the main component of the bacterial cell wall [1.1.1, 1.2.1]. These proteins are classified into high-molecular-weight (HMW) classes, such as PBP1 and PBP2, which possess transpeptidase and often transglycosylase activities required for cell division and elongation, and low-molecular-weight (LMW) classes, such as PBP4, which act as carboxypeptidases or endopeptidases involved in peptidoglycan cross-linking and maturation [1.1.3, 1.4.2]. PBPs are the primary therapeutic targets for beta-lactam antibiotics, including penicillins, cephalosporins, and carbapenems [1.2.2, 1.4.3]. These drugs function as suicide inhibitors by covalently binding to the active-site serine of the PBP transpeptidase domain, mimicking the D-alanyl-D-alanine substrate and forming a stable acyl-enzyme complex [1.2.1, 1.2.3]. This irreversible inhibition prevents the cross-linking of glycan strands, leading to a compromised cell wall, osmotic instability, and eventual bacterial lysis and death [1.2.1, 1.3.1]. Resistance to these antibiotics often occurs through the acquisition of low-affinity PBP variants, such as PBP2a in methicillin-resistant Staphylococcus aureus (MRSA), or through mutations and overexpression of native PBPs like PBP4 [1.1.1, 1.4.4].

Other names

DD-transpeptidasesPeptidoglycan synthasesMurein synthasesPenicillin-binding protein family

Beta-lactam antibiotics act as structural analogs of the D-alanyl-D-alanine terminus of peptidoglycan precursors and irreversibly inhibit the transpeptidase domain of PBPs by forming a covalent acyl-enzyme complex, thereby blocking cell wall cross-linking and causing bacterial lysis [1.2.1, 1.2.3].