A novel bi-functional chalcone inhibits multi-drug resistant Staphylococcus aureus and potentiates the activity of fluoroquinolones
| Autor: | Ranjana Pathania, Rashmi Gaur, Vivek Kumar Gupta, Atin Sharma, Mahak Saini, Rajendra Singh Bhakuni, Jawed Akther |
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| Rok vydání: | 2019 |
| Předmět: |
Methicillin-Resistant Staphylococcus aureus
Chalcone Cell Membrane Permeability medicine.drug_class Antibiotics Microbial Sensitivity Tests medicine.disease_cause 01 natural sciences Biochemistry Microbiology Mice chemistry.chemical_compound Chalcones Bacterial Proteins Drug Resistance Bacterial Drug Discovery Cell Adhesion medicine Animals Humans MTT assay Molecular Biology Norfloxacin 010405 organic chemistry Cell Membrane Organic Chemistry Drug Synergism Haemolysis Anti-Bacterial Agents 0104 chemical sciences 010404 medicinal & biomolecular chemistry HEK293 Cells chemistry Staphylococcus aureus Female Efflux Multidrug Resistance-Associated Proteins Isoliquiritigenin Fluoroquinolones medicine.drug |
| Zdroj: | Bioorganic Chemistry. 83:214-225 |
| ISSN: | 0045-2068 |
| DOI: | 10.1016/j.bioorg.2018.10.024 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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