Penicillin-binding protein 3 and 4 (PBP3 and PBP4) (PBP3/4)

Penicillin-binding proteins (PBPs) are a group of essential bacterial enzymes that catalyze the final steps of peptidoglycan synthesis, the primary component of the bacterial cell wall. Penicillin-binding protein 3 (PBP3), often referred to as FtsI in Gram-negative bacteria, is a high-molecular-weight transpeptidase specifically required for septum formation during cell division; its inhibition leads to the formation of long, non-dividing filaments and eventual cell lysis. Penicillin-binding protein 4 (PBP4) is typically a low-molecular-weight enzyme functioning as a carboxypeptidase or endopeptidase, though in certain pathogens like Staphylococcus aureus, it exhibits transpeptidase activity and is a critical determinant of resistance to next-generation beta-lactams. These proteins are the primary therapeutic targets for beta-lactam antibiotics, which act as structural analogs of the D-Ala-D-Ala peptide substrate to covalently inactivate the enzymes' active site serine. Understanding the specific roles of PBP3 and PBP4 is vital for overcoming antibiotic resistance, as mutations or altered expression of these proteins frequently mediate reduced susceptibility to clinical treatments.

Other names

FtsI (PBP3)DacB (PBP4)Peptidoglycan D-glutamyl-L-diaminopimelate endopeptidaseSeptum formation proteinD-alanyl-D-alanine carboxypeptidaseTranspeptidase PBP3Low-molecular-weight penicillin-binding protein 4

Inhibition of peptidoglycan cross-linking by covalently binding to the active site serine residue of the PBP, acting as a suicide substrate that prevents the formation of the bacterial cell wall and leads to osmotic instability and cell death.