Identification and Characterization of Indolebutyroyl Aspartic Acid: A Promising Inhibitor of VIM-2 Metallo--Lactamase Against Carbapenem-Resistant Pseudomonas aeruginosa Strains

 β-lactamases (BLs) are the leading cause of antimicrobial resistance in gram-negative bacteria. Metallo-β-lactamases (MBL) play a critical role in hydrolyzing a wide range of β-lactam drugs, including carbapenems. Recent reports have highlighted an increase in Pseudomonas aeruginosa abundance during acute SARS-CoV-2 infections, potentially complicating viral treatment.

 This study aims to present the discovery of novel inhibitors targeting P. aeruginosa Verona integrin-encoded (VIM)-2 MBL using a combination of computational and experimental methods.

 A total of 61 953 natural compounds and captopril (used as a positive control) were screened as potential inhibitors. Additionally, the 3D structure of the enzyme was obtained from the Protein Data Bank (PDB). The most promising compounds were selected through molecular docking, and further analysis of conformational changes in the protein-inhibitor complex was conducted using the GROMACS molecular dynamics package. Enzyme assays were performed to validate the results obtained through molecular modeling.

 Two compounds, namely ZINC98363781 and indolebutyroyl aspartic acid (ZINC04090499), demonstrated strong inhibitory potential with docking energies of -14.1 and -12.7 kcal mol-1, respectively. Captopril exhibited a docking energy of -10.684 kcal mol-1. Molecular dynamics analysis indicated good stability and flexibility in the studied systems. According to the binding energies calculated by mechanics-Poisson Boltzmann surface area (MM-PBSA), captopril, ZINC98363781, and ZINC04090499 displayed binding energies of -29.39 ± 5.92 kcal mol-1, -79.74 ± 67.51 kcal mol-1, and -99.65 ± 26.52 kcal mol-1, respectively. Enzyme assays confirmed that the IC50 value of ZINC04090499 against VIM-2 MBL was 25 μM.

 Our findings suggest that ZINC04090499 is a promising inhibitor of VIM-2 MBL and warrant further investigation in laboratory studies.