High-molecular-weight penicillin-binding protein (HMW PBP)

High-molecular-weight penicillin-binding proteins (HMW PBPs) are essential bacterial enzymes located on the outer surface of the cytoplasmic membrane, where they catalyze the final stages of peptidoglycan synthesis (StatPearls, NBK551630). These proteins are divided into Class A, which possess both transglycosylase and transpeptidase activities, and Class B, which function primarily as transpeptidases involved in cell shape and division (PubMed, PMID: 18218611). By facilitating the cross-linking of glycan chains, HMW PBPs like PBP1A and PBP1B ensure the structural integrity of the bacterial cell wall, which is vital for resisting osmotic pressure. They are the primary targets for beta-lactam antibiotics, which act as structural analogs of the D-Ala-D-Ala peptide substrate and form a stable acyl-enzyme complex that inhibits further cell wall construction (UniProt, P0AD65). This inhibition triggers autolytic pathways, resulting in cell lysis and death. Resistance to these agents often occurs through mutations in the PBP genes that decrease antibiotic affinity, a major mechanism in pathogens such as Streptococcus pneumoniae (PubMed, PMID: 22412004).

Other names

Penicillin-binding protein 1APBP1APenicillin-binding protein 1BPBP1BPenicillin-binding protein 2PBP2Penicillin-binding protein 3PBP3Murein polymerasePeptidoglycan glycosyltransferaseHigh molecular weight penicillin-binding proteins, primarily PBP1A and additional PBPs

Covalent inhibition of the transpeptidase domain by acylating the active-site serine residue, which prevents the cross-linking of peptidoglycan chains and leads to bacterial cell wall failure and lysis.