Abstract
Antibiotic resistance is one of the significant problems globally; there is an increase in resistance with introducing every new class of antibiotics. Further, this has become one of the reasons for arising of new resistance mechanisms in Acinetobacter baumannii. In this study, we have screened natural compounds as a possible inhibitor against the NDM-1 β-lactamase enzyme from A. baumannii using a combination of in silico methods and in vitro evaluation. The database of natural compounds was screened against NDM-1 protein, using Glide docking, followed by QM-polarised ligand docking (QPLD). When the screened hits were validated in vitro, withaferin A and mangiferin had good IC50 values in reducing the activity of NDM-1 enzymes, and their fractional inhibitory concentration index (FICI) was ascertained in combination with imipenem. The withaferin A and mangiferin-NDM-1 docking complexes were analyzed for structural stability by molecular dynamic simulation analysis using GROMACS for 100 ns. The molecular properties of the natural compounds were then calculated using density functional theory (DFT). Withaferin A and mangiferin showed promising inhibitory activity and can be a natural compound candidate inhibitor synergistically used along with carbapenems against NDM-1 producing A. baumannii.
Highlights
The worldwide increase in carbapenem resistance among Gram-negative bacteria has become a significant clinical concern
The overall quality factor predicted by the ERRAT server for the current 3D model was 84.40, and the VERIFY3D server predicted that 96.68% of the residues in New Delhi Metallo-β-lactamase 1 (NDM-1) had an average 3D-1D score > 0:2, indicating that the model was valid
This study focused on identifying potential inhibitors targeting β-lactamases with carbapenem as substrate, using molecular docking, molecular dynamic modeling, in silico pharmacokinetics, and quantum chemical analysis on a collection of over two hundred phytochemical compounds
Summary
The worldwide increase in carbapenem resistance among Gram-negative bacteria has become a significant clinical concern. Acinetobacter is one such species that showed high resistance after just four years of its identification in 1971 and as early as the 1990s. They were resistant to imipenem, the trusted drug of choice [1] [2]. There are three subclasses under the Metallo β-lactamases, B1, B2, and B3; the New Delhi Metallo-β-lactamase 1 (NDM-1) belongs to B1. NDM-1 is an emerging concern among the heterogeneous group of carbapenemases, first described from Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, A. baumannii, and, more recently, Enterobacteriaceae [4] [5] [6]
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