Penicillin-binding protein 1c and penicillin-binding protein 3 (PBP1c/PBP3)

Penicillin-binding proteins 1c (PBP1c) and 3 (PBP3) are membrane-anchored enzymes in Escherichia coli that are essential for the synthesis and maintenance of the peptidoglycan cell wall [1, 10]. PBP3, also known as FtsI, is a class B monofunctional transpeptidase that is critical for the formation of the division septum during bacterial cell division; its inhibition by beta-lactam antibiotics leads to cell filamentation and eventual lysis [9, 11]. PBP1c, encoded by the pbpC (or mrcB) gene, is a class A bifunctional enzyme with both transglycosylase and transpeptidase activities, although it is generally considered non-essential under standard growth conditions and may serve an auxiliary role in cell wall assembly [6, 8]. These proteins are the primary therapeutic targets for various beta-lactam antibiotics, which act as substrate mimics to irreversibly inhibit the transpeptidase domain [12, 22]. Drugs such as ceftolozane and aztreonam exhibit high affinity for PBP3, while ceftolozane is also noted for its binding to PBP1c, contributing to its efficacy against resistant Gram-negative pathogens [3, 4]. Clinical resistance to these agents is a major challenge, often driven by the production of beta-lactamases or the emergence of specific mutations and amino acid insertions (e.g., YRIN or YRIK) in the PBP3 sequence that reduce drug binding affinity [3, 15].

Other names

PBP1cPBP3MrcBFtsIpbpCftsIpbpBPenicillin-binding protein 1CPenicillin-binding protein 3Septum formation protein IPeptidoglycan glycosyltransferase/transpeptidase 1C

Inhibition of peptidoglycan transpeptidation and transglycosylation by acting as a structural analog of the D-alanyl-D-alanine terminus of peptidoglycan precursors, leading to irreversible acylation of the active-site serine and subsequent cell wall failure [12, 22].