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

Abstract

Antibiotic resistance (AR) remains one of the leading global health challenges, mostly implicated in disease-related deaths. The Enterobacteriaceae-producing metallo-b-lactamases (MBLs) are critically involved in AR pathogenesis through Zn-dependent catalytic destruction of b-lactam antibiotics, yet with limited successful clinical inhibitors. The efficacy of relevant broad-spectrum b-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-b-lactam scaffolds, tenable to resist catalytic hydrolysis. They displayed ideal drug-like ADMET properties, thus, representing putative Znsensitive non-b-lactam inhibitors of IMP-1 amenable for further experimental studies