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4‐Hydroxy‐ α ‐Tetralone and its Derivative as Drug Resistance Reversal Agents in Multi Drug Resistant E scherichia coli
Author(s) -
Dwivedi Gaurav R.,
Upadhyay Harish C.,
Yadav Dharmendra K.,
Singh Vigyasa,
Srivastava Santosh K.,
Khan Feroz,
Darmwal Nandan S.,
Darokar Mahendra P.
Publication year - 2014
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12263
Subject(s) - efflux , multiple drug resistance , tetracycline , chemistry , escherichia coli , drug resistance , in silico , atp binding cassette transporter , antibacterial activity , docking (animal) , p glycoprotein , transporter , pharmacology , biochemistry , microbiology and biotechnology , biology , bacteria , antibiotics , gene , medicine , genetics , nursing
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 ( yoj I) 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.