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Please use this identifier to cite or link to this item: http://repository.iitr.ac.in/handle/123456789/1248
Title: A novel bi-functional chalcone inhibits multi-drug resistant Staphylococcus aureus and potentiates the activity of fluoroquinolones
Authors: Gupta V.K.
Gaur R.
Sharma A.
Akther J.
Saini M.
Bhakuni R.S.
Pathania R.
Published in: Bioorganic Chemistry
Abstract: Staphylococcus aureus is the leading cause of bacteraemia and the dwindling supply of effective antibacterials has exacerbated the problem of managing infections caused by this bacterium. Isoliquiritigenin (ISL) is a plant flavonoid that displays therapeutic potential against S. aureus. The present study identified a novel mannich base derivatives of ISL, IMRG4, active against Vancomycin intermediate S. aureus (VISA). IMRG4 damages the bacterial membranes causing membrane depolarization and permeabilization, as determined by loss of salt tolerance, flow cytometric analysis, propidium idodie and fluorescent microscopy. It reduces the intracellular invasion of HEK-293 cells by S. aureus and decreases the staphylococcal load in different organs of infected mice models. In addition to anti-staphylococcal activity, IMRG4 inhibits the multidrug efflux pump, NorA, which was determined by molecular docking and EtBr efflux assays. In combination, IMRG4 significantly reduces the MIC of norfloxacin for clinical strains of S. aureus including VISA. Development of resistance against IMRG4 alone and in combination with norfloxacin was low and IMRG4 prolongs the post-antibiotic effect of norfloxacin. These virtues combined with the low toxicity of IMRG4, assessed by MTT assay and haemolysis, makes it an ideal candidate to enter drug development pipeline against S. aureus. © 2018 Elsevier Inc.
Citation: Bioorganic Chemistry (2019), 83(): 214-225
URI: https://doi.org/10.1016/j.bioorg.2018.10.024
http://repository.iitr.ac.in/handle/123456789/1248
Issue Date: 2019
Publisher: Academic Press Inc.
Keywords: Antibacterial
Efflux pump inhibitor
Membrane disruption
Natural products
Proton motive force
ISSN: 452068
Author Scopus IDs: 57196262614
36604273700
57217481823
57204467404
57204465219
6701502246
7004308029
Author Affiliations: Gupta, V.K., Molecular Bacteriology and Chemical Genetics Lab, Department of Biotechnology, Indian Institute of Technology Roorkee, District HaridwarUttarakhand 247667, India
Gaur, R., Medicinal Chemistry Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, 226015, India
Sharma, A., Molecular Bacteriology and Chemical Genetics Lab, Department of Biotechnology, Indian Institute of Technology Roorkee, District HaridwarUttarakhand 247667, India
Akther, J., Molecular Bacteriology and Chemical Genetics Lab, Department of Biotechnology, Indian Institute of Technology Roorkee, District HaridwarUttarakhand 247667, India
Saini, M., Molecular Bacteriology and Chemical Genetics Lab, Department of Biotechnology, Indian Institute of Technology Roorkee, District HaridwarUttarakhand 247667, India
Bhakuni, R.S., Medicinal Chemistry Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, 226015, India
Pathania, R., Molecular Bacteriology and Chemical Genetics Lab, Department of Biotechnology, Indian Institute of Technology Roorkee, District HaridwarUttarakhand 247667, India
Funding Details: This work was supported by DST SERB NPDF grant no. PDF/2016/000065 to V.K.G with R.P. as mentor. J.A. is financially supported by Indian Council of Medical Research, India .
Corresponding Author: Pathania, R.; Department of Biotechnology, Indian Institute of Technology RoorkeeIndia; email: rpathfbs@iitr.ac.in
Appears in Collections:Journal Publications [BT]

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