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.

Unprecedented Oxidative Addition and Metal‐Only Lewis Pair Chemistry of Antimony Trihalides

“…It was interesting to note that TET showed antibacterial activity at a very low concentration when used in combination with phytol derivatives 4 , 9 , 10 , 11 , and 14 (Figure 1). Accumulation and efflux of ethidium bromide are good indicators of the involvement of efflux pumps in a resistance mechanism, particularly in Gram‐negative bacteria such as E coli 33. 34 To evaluate a possible efflux pump inhibition mechanism for derivatives 4 , 9 , 10 , 11 , and 14 , these compounds were subjected to a fluorescence‐based ethidium bromide efflux assay using MDREC‐KG4.…”

Drug Resistance Reversal Potential of Ursolic Acid Derivatives against Nalidixic Acid‐ and Multidrug‐resistant Escherichia coli

“…The real-time quantification of the RNA template was analyzed by SYBR GreenER qPCR supermix (Invitrogen, Carlsbad, CA, USA) using 7900HT fast real-time PCR system (Invitrogen). Observations were recorded in terms of LogRQ after normalization of indigenous gene coding for D-glyceraldehyde-3-phosphate-dehydrogenase (gapdh) (13,24).…”

“…In continuation of our work on synergistic potential of some natural product and their derivatives , this study describes drug resistance reversal potential of ursolic acid derivatives in combination with nalidixic acid and tetracycline. The most active derivatives of ursolic acid (UA) were further investigated in detail using efflux pump inhibition assay, ATPase inhibition assay, real time expression analysis, in silico docking and ADMET analysis.…”

Arenophile‐Mediated Dearomative Reduction

“…Similarly, the urazole moiety was replaced with an endoper oxide that underwent an in situ Kornblum-DeLaMare rearrangement [23] to deliver γ-hydroxytetralone 15 . This reaction sequence exemplifies the production of an expensive bioactive natural product 15 [24] ($577 g −1 , Aldrich) from a cheap feedstock naphthalene ( 6a , $0.03 g −1 ) in two one-pot chemical operations.…”