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Antibiotic resistance (AR) remains one of the leading global health challenges, mostly implicated in disease-related deaths. The  Enterobacteriaceae -producing metallo-β-lactamases (MBLs) are critically involved in AR pathogenesis through Zn-dependent catalytic destruction of β-lactam antibiotics, yet with limited successful clinical inhibitors. The efficacy of relevant broad-spectrum β-lactams including imipenem and meropenem are seriously challenged by their susceptibility to the Zn-dependent carbapenemase hydrolysis, as such, searching for alternatives remains imperative. In this study, computational molecular modelling and virtual screening methods were extensively applied to identify new putative Zn-sensitive broad-spectrum inhibitors of MBLs, specifically imipenemase-1 (IMP-1) from the IBScreen database. Three ligands,  STOCK3S-30154 ,  STOCK3S-30418  and  STOCK3S-30514  selectively displayed stronger binding interactions with the enzymes compared to reference inhibitors,  imipenem  and  meropenem . For instance, the ligands showed molecular docking scores of −9.450, −8.005 and −10.159 kcal/mol, and MM-GBSA values of −40.404, −31.902 and −33.680 kcal/mol respectively against the IMP-1. Whereas,  imipenem  and  meropenem  showed docking scores of −9.038 and −10.875 kcal/mol, and MM-GBSA of −31.184 and −32.330 kcal/mol respectively against the enzyme. The ligands demonstrated good thermodynamic stability and compactness in complexes with IMP-1 throughout the 100 ns molecular dynamics (MD) trajectories. Interestingly, their binding affinities and stabilities were significantly affected in contacts with the remodelled Zn-deficient IMP-1, indicating sensitivity to the carbapenemase active Zn site, however, with non-β-lactam scaffolds, tenable to resist catalytic hydrolysis. They displayed ideal drug-like ADMET properties, thus, representing putative Zn-sensitive non-β-lactam inhibitors of IMP-1 amenable for further experimental studies.

Computational modelling of potential Zn-sensitive non-β-lactam inhibitors of imipenemase-1 (IMP-1)