In Silico and In Vitro Screening of Natural Compounds as Broad-Spectrum β-Lactamase Inhibitors against Acinetobacter baumannii New Delhi Metallo-β-lactamase-1 (NDM-1)

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.

A Computational Exploration of Whole Genome Sequences of Klebsiella pneumoniae ST16 for Beta-lactam Resistance and the Discovery of NMD-1 Resistance Gene Inhibitor

“…Baicalein complex were generally lower than those of the Adapalene-NDM-1 complex, indicating that Baicalein may induce a more stable conformation of NDM-1 compared to Adapalene. This observation is inconsistent with a previous study by Vasudevan et al [44], where lesser uctuation was observed.…”

Cracking the Code of Antibiotic Resistance OF Klebsiella pneumoniae ST16: A Computational Exploration of Whole Genome Sequences for Beta-lactam Resistance and the Discovery of NMD-1 Resistance Gene Inhibitor

“…Our analysis revealed that the RMSF values for the Baicalein-NDM-1 complex were generally lower than those of the Adapalene-NDM-1 complex, indicating that Baicalein may induce a more stable conformation of NDM-1 compared to Adapalene. This observation is inconsistent with a previous study by Vasudevan et al [32], where lesser uctuation was observed [32] Rg is a measure of the compactness of the protein structure, and it re ects the overall size and shape of the protein. The uctuations in Rg during MD simulation can provide insights into the conformational changes and exibility of the protein complex.…”

Phenotypic, molecular, and in silico characterization of coumarin as carbapenemase inhibitor to fight carbapenem-resistant Klebsiella pneumoniae

“…Similarly, a molecular docking study on the phenolic compound mangiferin showed that mangiferin interacted with NDM-1 catalytic amino acid residues through hydrogen bonding and hydrophobic interactions. Mangiferin was found to have a good docking score (-9.12 Kcal/mol) with NDM-1, compared to a docking score of -8.77 Kcal/mol for meropenem, indicating the possible biological activity of mangiferin as a carbapenemase inhibitor [63].…”