Neisseria gonorrhoeae Penicillin-binding protein 2 (PBP2)

Neisseria gonorrhoeae Penicillin-binding protein 2 (PBP2) is an essential Class B transpeptidase encoded by the penA gene [1, 2]. It plays a critical role in the final stages of peptidoglycan biosynthesis by catalyzing the cross-linking of glycan strands, a process vital for maintaining the structural integrity of the bacterial cell wall and supporting cell division [5, 11, 15]. PBP2 is the primary lethal target for beta-lactam antibiotics, including penicillins and extended-spectrum cephalosporins like ceftriaxone, which is currently the first-line treatment for gonorrhea [1, 13]. The clinical utility of drugs targeting PBP2 is increasingly compromised by the emergence of multidrug-resistant (MDR) strains [9, 12]. Resistance primarily arises through the acquisition of mosaic penA alleles via horizontal gene transfer from commensal Neisseria species [2, 6]. These alleles contain numerous mutations that alter the protein's conformational dynamics, specifically the beta3-beta4 loop, reducing the affinity for beta-lactams while preserving enough transpeptidase activity for bacterial survival [1, 4]. Consequently, there is an urgent need for novel non-beta-lactam inhibitors, such as boronate-based compounds like VNRX-14079, that can effectively target these resistant PBP2 variants [8, 10]. Understanding the structural basis of PBP2 resistance is essential for the development of next-generation anti-gonococcal therapies [3, 7].

Other names

penAPenicillin-binding protein 2Class B PBPTranspeptidase

Inhibition of peptidoglycan transpeptidase activity, preventing cell wall cross-linking and leading to bacterial lysis [5, 11, 13]