Potential inhibitors designed against NDM-1 type metallo-β-lactamases: an attempt to enhance efficacies of antibiotics against multi-drug-resistant bacteria

Abstract NDM-1 and its variants are the most prevalent types of metallo-β-lactamases, hydrolyze almost all antibiotics of β-lactam group leading to multiple-drug resistance in bacteria. No inhibitor has yet been obtained for NDM-1 or other class of metallo-β-lactamases. Therefore, strategies to iden...

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Autores principales:	Asad U. Khan, Abid Ali, Danishuddin, Gaurava Srivastava, Ashok Sharma
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d569fc2d69154ea9b88d4c0fc50a6d67
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spelling	oai:doaj.org-article:d569fc2d69154ea9b88d4c0fc50a6d672021-12-02T12:32:29ZPotential inhibitors designed against NDM-1 type metallo-β-lactamases: an attempt to enhance efficacies of antibiotics against multi-drug-resistant bacteria10.1038/s41598-017-09588-12045-2322https://doaj.org/article/d569fc2d69154ea9b88d4c0fc50a6d672017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-09588-1https://doaj.org/toc/2045-2322Abstract NDM-1 and its variants are the most prevalent types of metallo-β-lactamases, hydrolyze almost all antibiotics of β-lactam group leading to multiple-drug resistance in bacteria. No inhibitor has yet been obtained for NDM-1 or other class of metallo-β-lactamases. Therefore, strategies to identify novel anti-β-lactamase agents with specific mechanisms of action are the need of an hour. In this study, we have reported the discovery of novel non-β-lactam inhibitors against NDM-1 by multi-step virtual screening approach. The potential for virtually screened drugs was estimated through in vitro cell assays. Five chemical compounds were finally purchased and evaluated experimentally for their efficacies to inhibit NDM-1 producing bacterial cells, in vitro. The dissociation constants (Kd), association constant (Ka), stoichiometry (n) and binding energies (ΔG) of compounds with the respective targets were determined using isothermal titration calorimetry (ITC). Molecular dynamic simulation carried out for 25 ns revealed that these complexes were stable throughout the simulation with relative RMSD in acceptable range. Moreover, Microbiological and kinetic studies further confirmed high efficacies of these inhibitors by reducing the minimum inhibitory concentration (MIC) and catalysis of antibiotics by β-lactamases in the presence of inhibitors. Therefore, we conclude that these potential inhibitors may be used as lead molecules for future drug candidates.Asad U. KhanAbid AliDanishuddinGaurava SrivastavaAshok SharmaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Asad U. Khan Abid Ali Danishuddin Gaurava Srivastava Ashok Sharma Potential inhibitors designed against NDM-1 type metallo-β-lactamases: an attempt to enhance efficacies of antibiotics against multi-drug-resistant bacteria
description	Abstract NDM-1 and its variants are the most prevalent types of metallo-β-lactamases, hydrolyze almost all antibiotics of β-lactam group leading to multiple-drug resistance in bacteria. No inhibitor has yet been obtained for NDM-1 or other class of metallo-β-lactamases. Therefore, strategies to identify novel anti-β-lactamase agents with specific mechanisms of action are the need of an hour. In this study, we have reported the discovery of novel non-β-lactam inhibitors against NDM-1 by multi-step virtual screening approach. The potential for virtually screened drugs was estimated through in vitro cell assays. Five chemical compounds were finally purchased and evaluated experimentally for their efficacies to inhibit NDM-1 producing bacterial cells, in vitro. The dissociation constants (Kd), association constant (Ka), stoichiometry (n) and binding energies (ΔG) of compounds with the respective targets were determined using isothermal titration calorimetry (ITC). Molecular dynamic simulation carried out for 25 ns revealed that these complexes were stable throughout the simulation with relative RMSD in acceptable range. Moreover, Microbiological and kinetic studies further confirmed high efficacies of these inhibitors by reducing the minimum inhibitory concentration (MIC) and catalysis of antibiotics by β-lactamases in the presence of inhibitors. Therefore, we conclude that these potential inhibitors may be used as lead molecules for future drug candidates.
format	article
author	Asad U. Khan Abid Ali Danishuddin Gaurava Srivastava Ashok Sharma
author_facet	Asad U. Khan Abid Ali Danishuddin Gaurava Srivastava Ashok Sharma
author_sort	Asad U. Khan
title	Potential inhibitors designed against NDM-1 type metallo-β-lactamases: an attempt to enhance efficacies of antibiotics against multi-drug-resistant bacteria
title_short	Potential inhibitors designed against NDM-1 type metallo-β-lactamases: an attempt to enhance efficacies of antibiotics against multi-drug-resistant bacteria
title_full	Potential inhibitors designed against NDM-1 type metallo-β-lactamases: an attempt to enhance efficacies of antibiotics against multi-drug-resistant bacteria
title_fullStr	Potential inhibitors designed against NDM-1 type metallo-β-lactamases: an attempt to enhance efficacies of antibiotics against multi-drug-resistant bacteria
title_full_unstemmed	Potential inhibitors designed against NDM-1 type metallo-β-lactamases: an attempt to enhance efficacies of antibiotics against multi-drug-resistant bacteria
title_sort	potential inhibitors designed against ndm-1 type metallo-β-lactamases: an attempt to enhance efficacies of antibiotics against multi-drug-resistant bacteria
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/d569fc2d69154ea9b88d4c0fc50a6d67
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Potential inhibitors designed against NDM-1 type metallo-β-lactamases: an attempt to enhance efficacies of antibiotics against multi-drug-resistant bacteria

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