Dataset Information

Inhibitory Potential of Polyclonal Camel Antibodies against New Delhi Metallo-?-lactamase-1 (NDM-1).

ABSTRACT: New Delhi Metallo-?-lactamase-1 (NDM-1) is the most prevalent type of metallo-?-lactamase, able to hydrolyze almost all antibiotics of the ?-lactam group, leading to multidrug-resistant bacteria. To date, there are no clinically relevant inhibitors to fight NDM-1. The use of dromedary polyclonal antibody inhibitors against NDM-1 represents a promising new class of molecules with inhibitory activity. In the current study, immunoreactivities of dromedary Immunoglobulin G (IgG) isotypes containing heavy-chain and conventional antibodies were tested after successful immunization of dromedary using increasing amounts of the recombinant NDM-1 enzyme. Inhibition kinetic assays, performed using a spectrophotometric method with nitrocefin as a reporter substrate, demonstrated that IgG1, IgG2, and IgG3 were able to inhibit not only the hydrolytic activity of NDM-1 but also Verona integron-encoded metallo-?-lactamase (VIM-1) (subclass B1) and L1 metallo-?-lactamase (L1) (subclass B3) with inhibitory concentration (IC50) values ranging from 100 to 0.04 ?M. Investigations on the ability of IgG subclasses to reduce the growth of recombinant Escherichia coli BL21(DE3)/codon plus cells containing the recombinant plasmid expressing NDM-1, L1, or VIM-1 showed that the addition of IgGs (4 and 8 mg/L) to the cell culture was unable to restore the susceptibility of carbapenems. Interestingly, IgGs were able to interact with NDM-1, L1, and VIM-1 when tested on the periplasm extract of each cultured strain. The inhibitory concentration was in the micromolar range for all ?-lactams tested. A visualization of the 3D structural basis using the three enzyme Protein Data Bank (PDB) files supports preliminarily the recorded inhibition of the three MBLs.

SUBMITTER: Ben Abderrazek R

PROVIDER: S-EPMC7584030 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Inhibitory Potential of Polyclonal Camel Antibodies against New Delhi Metallo-β-lactamase-1 (NDM-1).

Ben Abderrazek Rahma R Chammam Sarra S Ksouri Ayoub A Perilli Mariagrazia M Dhaouadi Sayda S Mdini Ines I Benlasfar Zakaria Z Amicosante Gianfranco G Bouhaouala-Zahar Balkiss B Piccirilli Alessandra A

Molecules (Basel, Switzerland) 20200928 19

New Delhi Metallo-β-lactamase-1 (NDM-1) is the most prevalent type of metallo-β-lactamase, able to hydrolyze almost all antibiotics of the β-lactam group, leading to multidrug-resistant bacteria. To date, there are no clinically relevant inhibitors to fight NDM-1. The use of dromedary polyclonal antibody inhibitors against NDM-1 represents a promising new class of molecules with inhibitory activity. In the current study, immunoreactivities of dromedary Immunoglobulin G (IgG) isotypes containing ...[more]

PMID: 32998307

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Project description:The effectiveness of all antibiotics in the β-lactam group to cure bacterial infections has been impaired by the introduction of the New Delhi Metallo-β-lactamase (NDM-1) enzyme. Attempts have been made to discover a potent chemical as an inhibitor to this enzyme in order to restore the efficacy of antibiotics. However, it has been a challenging task to develop broad-spectrum inhibitors of metallo-β-lactamases. Lack of sequence homology across metallo-β-lactamases (MBLs), the rapidly evolving active site of the enzyme, and structural similarities between human enzymes and metallo-β-lactamases, are the primary causes for the difficulty in the development of these inhibitors. Therefore, it is imperative to concentrate on the discovery of an effective NDM-1 inhibitor. This study used various in silico approaches, including molecular docking and molecular dynamics simulations, to investigate the potential of phytochemicals to inhibit the NDM-1 enzyme. For this purpose, a library of about 59,000 phytochemicals was created from the literature and other databases, including FoodB, IMPPAT, and Phenol-Explorer. A physiochemical and pharmacokinetics analysis was performed to determine possible toxicity and mutagenicity of the ligands. Following the virtual screening, phytochemicals were assessed for their binding with NDM-1using docking scores, RMSD values, and other critical parameters. The docking score was determined by selecting the best conformation of the protein-ligand complex. Three phytochemicals, i.e., butein (polyphenol), monodemethylcurcumin (polyphenol), and rosmarinic acid (polyphenol) were identified as result of pharmacokinetics and molecular docking studies. Furthermore, molecular dynamics simulations were performed to determine structural stabilities of the protein-ligand complexes. Monodemethylcurcumin, butein, and rosmarinic acid were identified as potential inhibitors of NDM-1 based on their low RMSD, RMSF, hydrogen bond count, average Coulomb-Schrödinger interaction energy, and Lennard-Jones-Schrödinger interaction energy. The present investigation suggested that these phytochemicals might be promising candidates for future NDM-1 medication development to respond to antibiotic resistance.

Dataset Information

Inhibitory Potential of Polyclonal Camel Antibodies against New Delhi Metallo-?-lactamase-1 (NDM-1).

Publications

Inhibitory Potential of Polyclonal Camel Antibodies against New Delhi Metallo-β-lactamase-1 (NDM-1).

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