Penicillin-binding protein 3 (Acinetobacter baumannii) (PBP3)

Penicillin-binding protein 3 (PBP3), encoded by the ftsI gene, is an essential high-molecular-mass transpeptidase in Acinetobacter baumannii that is primarily responsible for peptidoglycan synthesis at the division septum. As a Class B PBP, it plays a critical role in bacterial cell division; its inhibition leads to filamentation and cell death. PBP3 is a primary therapeutic target for many beta-lactam antibiotics, including carbapenems and the monobactam aztreonam, which are often the last line of defense against multidrug-resistant (MDR) A. baumannii infections. In recent years, PBP3 has gained significant attention due to the emergence of resistance mutations, particularly insertions near the active site that reduce the affinity of clinical antibiotics. Modern drug development strategies often focus on combining PBP3 inhibitors with novel beta-lactamase inhibitors, such as durlobactam or zidebactam, to overcome existing resistance mechanisms in this high-priority pathogen.

Other names

PBP-3FtsIPeptidoglycan D-amino acid transpeptidaseD-alanyl-D-alanine transpeptidaseSeptal peptidoglycan synthase

Beta-lactam antibiotics and diazabicyclooctane (DBO) inhibitors covalently bind to the active-site serine residue of PBP3, inhibiting its transpeptidase activity. This prevents the cross-linking of peptidoglycan chains during cell division, leading to the formation of long filaments, cell wall instability, and eventual bacterial lysis.