title: 4-Hydroxy-α-tetralone and its derivative as drug resistance reversal agents in multi drug resistant Escherichia coli.
abstract: The purpose of present investigation was to understand the drug resistance reversal mechanism of 4-hydroxy-α-tetralone (1) isolated from Ammannia spp. along with its semi-synthetic derivatives (1a-1e) using multidrug resistant Escherichia coli (MDREC). The test compounds did not show significant antibacterial activity of their own, but in combination, they reduced the minimum inhibitory concentration (MIC) of tetracycline (TET). In time kill assay, compound 1 and its derivative 1e in combination with TET reduced the cell viability in concentration dependent manner. Compounds 1 and 1e were also able to reduce the mutation prevention concentration of TET. Both compounds showed inhibition of ATP dependent efflux pumps. In real time polymerase chain reaction (RT-PCR) study, compounds 1 and 1e alone and in combination with TET showed significant down expression of efflux pump gene (yojI) encoding multidrug ATP binding cassettes (ABC) transporter protein. Molecular mechanism was also supported by the in silico docking studies, which revealed significant binding affinity of compounds 1 and 1e with YojI. This study confirms that compound 1 and its derivative 1e are ABC efflux pump inhibitors which may be the basis for development of antibacterial combinations for the management of MDR infections from inexpensive natural product.
authors.affiliation: Molecular Bioprospection Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Kukrail Picnic Spot Road, P.O. CIMAP, Lucknow, 226015, India.
authors.forename: Gaurav R
authors.initials: GR
authors.lastname: Dwivedi
authors.forename: Harish C
authors.initials: HC
authors.lastname: Upadhyay
authors.forename: Dharmendra K
authors.initials: DK
authors.lastname: Yadav
authors.forename: Vigyasa
authors.initials: V
authors.lastname: Singh
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Srivastava
authors.forename: Feroz
authors.initials: F
authors.lastname: Khan
authors.forename: Nandan S
authors.initials: NS
authors.lastname: Darmwal
authors.forename: Mahendra P
authors.initials: MP
authors.lastname: Darokar
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D004926:Escherichia coli / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D044024:Tetralones / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C572587:4-hydroxy-alpha-tetralone; D000900:Anti-Bacterial Agents; D044024:Tetralones
keywords: 4-hydroxy-α-tetralone; ABC transporters; drug resistance reversal; efflux pump; in silico docking; multidrug resistant Escherichia coli