Nacubactam: a review on mechanistic insights and therapeutic promise for combating β-lactam resistance among multidrug-resistant Gram-negative pathogens

The unprecedented rise of antimicrobial resistance has substantially compromised the efficacy of β-lactam antibiotics, once the cornerstone of bacterial infection management, posing a major challenge to modern medicine. β-Lactams exert their antibacterial effect by inhibiting penicillin-binding proteins (PBPs) involved in cell wall synthesis; however, resistance mechanisms including porin alterations, PBP mutations, β-lactamase production, and efflux systems increasingly limit their clinical utility. In response, the development of β-lactamase inhibitors (BLIs) has become a critical strategy, with diazabicyclooctanes such as nacubactam (NAC) representing a mechanistically distinct advancement. NAC is a non-β-lactam BLI that exhibits a unique multi-modal mechanism of action encompassing inhibition of serine β-lactamases (Ambler classes A, C, and selected D), direct binding to penicillin-binding protein 2 (PBP2), and enhancement of partner β-lactam activity, including in certain β-lactamase-negative strains. Preclinical in vitro and in vivo studies demonstrate that NAC, when combined with β-lactams such as cefepime, aztreonam, or meropenem, produces substantial reductions in minimum inhibitory concentrations against multidrug-resistant Gram-negative pathogens, including carbapenemase-producing and metallo-β-lactamase (MBL)-coexpressing Enterobacterales. PBP2 targeting contributes to characteristic morphological changes and intrinsic antibacterial activity, resulting in synergistic cell wall disruption when used in combination regimens. Early clinical data from phase I studies indicate that NAC is generally well tolerated, with favorable pharmacokinetic properties and no serious safety concerns reported to date. Nevertheless, NAC lacks direct activity against class B MBLs and exhibits limited efficacy against certain non-fermenting Gram-negative organisms. Moreover, resistance mediated by β-lactamase or PBP2 alterations remains a potential concern. Importantly, robust human efficacy data from phase II and III clinical trials are currently limited. NAC represents a promising investigational BLI with a mechanistically innovative profile and broad β-lactam-potentiating capacity. While preclinical and early clinical findings support its translational potential, further clinical validation is required to define its therapeutic role, optimal combinations, and long-term impact in the management of multidrug-resistant Gram-negative infections.