Penicillin-binding protein 1 (PBP1) (PBP1)

Penicillin-binding protein 1 (PBP1) is a critical enzyme family involved in the final stages of bacterial peptidoglycan biosynthesis, essential for maintaining cell wall integrity and facilitating cell division [1, 2]. In many bacteria, such as Escherichia coli and Streptococcus pneumoniae, PBP1 exists as multiple isoforms (e.g., PBP1a and PBP1b) that function as bifunctional class A enzymes, possessing both glycosyltransferase activity for glycan chain polymerization and transpeptidase activity for peptide cross-linking [5, 7, 8]. In other pathogens like Staphylococcus aureus, PBP1 is a monofunctional class B transpeptidase that is essential for septal plate formation and cell viability [15]. As the primary target of beta-lactam antibiotics, PBP1 is inhibited when these drugs covalently bind to the active site serine of the transpeptidase domain, mimicking the natural D-alanyl-D-alanine substrate and preventing the formation of a stable cell wall [2, 4]. This inhibition leads to structural defects, osmotic instability, and eventual bacterial cell lysis [2, 16]. Clinical challenges associated with PBP1 include the emergence of resistance through target mutations or the acquisition of low-affinity variants, necessitating the development of novel inhibitors and synergistic drug combinations [4, 9, 14].

Other names

Penicillin-binding protein 1aPenicillin-binding protein 1bPBP1aPBP1bPBP-1ponAponBmrcAmrcBDD-transpeptidase 1aDD-transpeptidase 1bBacterial penicillin-binding proteins

Covalent inhibition of the transpeptidase domain via acylation of the active site serine, mimicking the D-alanyl-D-alanine substrate to prevent peptidoglycan cross-linking and cause cell lysis.