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-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.

Graphical Abstract

Communicated by Ramaswamy H. Sarma

Keywords:

• Antibiotic resistance
• metallo-β-lactamase
• virtual drug design
• molecular dynamics
• imipenemase
• Zn-chelating inhibitors

Author contributions

The manuscript was written with the contributions of all authors. All authors have approved the final version of the manuscript. Conceptualization, literature survey, data collection and writing by YOA, data collection and writing by AI, WAA and AL, research supervision and manuscript revision by MNM and HP.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This work was financially supported by the Tertiary Education Fund Nigeria and Fundamental Research Grant Scheme, Ministry of Higher Education of Malaysia (grant no. 203.CDADAH.6711955). YOA is thankful to the Institute of Postgraduate Studies, Universiti Sains Malaysia for GA Scheme (grant no. 308.AIPS.415401).