Discovery of a Potent Inhibitor to Overcome Carbapenem Resistance in Pseudomonas aeruginosa Strains via Inhibition of VIM-2 Metallo-β-lactamases

Abstract

Background: Mutations in bacteria frequently occur that display a crucial need for new antimicrobial agents. Metallo-β-lactamases (MBLs) are a growing threat to maintaining the effectiveness of beta-lactam antibiotics. Resistance to beta-lactam antibiotics is one of the most common types of antibiotic resistance, which causes the ineffectiveness of antibiotics. Objectives: This study aimed to identify a novel inhibitor using molecular dynamics simulations to inhibit VIM-2 Metallo-β-lactamases and overcome carbapenem resistance in Pseudomonas aeruginosa strains. Methods: Computational biology tools were employed for this study, including molecular dynamics, binding free energy, virtual screening, and docking. Natural compounds were taken from the ZINC databank and prepared. At the next stage, the prepared compounds were screened based on docking energy in the active site of VIM-2 MBL by Schrödinger (Maestro) software, and better compounds were selected. Captopril was chosen as a positive control inhibitor for VIM-2 MBLs. Ultimately, molecular dynamics simulations were performed using GROMACS software, and outputs were analyzed. Results: Maestro software's screening results showed that ZINC00517765 was the best inhibitor with -12.29 kcal mol-1 docking energy. The ADME investigations revealed that ZINC00517765 had an appropriate range of pharmacokinetics, lipophilicity, and drug-likeness features as an inhibitor of VIM-2 MBL. Molecular dynamics outcomes explicated that VIM-2 MBL in the presence of ZINC00517765 had better stability during simulation. The results of the MM-PBSA study illustrated that ZINC00517765 with -72.29 kJ mol-1 binding free energy was more potent than Captopril with -23.39 kJ mol-1. Conclusions: This study showed that VIM-2 MBL in the presence of ZINC00517765 has suitable stability during simulation. Also, more hydrogen bonds and stronger binding free energy than Captopril confirm that ZINC00517765 is a proper candidate for further studies and laboratory investigation.