Pimozide Inhibits the AcrAB-TolC Efflux Pump in Escherichia coli



Jürgen A Bohnert* , Sabine Schuster , Winfried V Kern
Center for Infectious Diseases and Travel Medicine, University Hospital, and Department of Medicine, Albert-Ludwigs-University, Freiburg, Germany


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© Bohnert et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

* Address correspondence to this athour at the University Hospital, Hugstetter Strasse 55, D-79106 Freiburg, Germany; Tel: +49-761- 270 18190; Fax: ++49-761-270 18200; E-mail: juergen@bohnert.name


Abstract

Efflux pump inhibitors (EPIs) are attractive compounds to reverse multidrug-resistance in clinically relevant bacterial pathogens. In this study we tested the ability of the neuroleptic drug pimozide to inhibit the Escherichia coli AcrAB-TolC efflux pump, whose overproduction confers resistance to various antimicrobial agents. A real-time Nile red efflux assay in the AcrAB – overproducing strain 3-AG100 revealed that pimozide was capable of full inhibition of this pump at a concentration of 100 µM, which is far below its intrinsic MIC (>1mM). However, MIC assay demonstrated very little effect of pimozide with regard to reduction in MICs of various antimicrobial compounds.

Only oxacillin MICs were reduced twofold in the presence of pimozide at 100 and 200 µM.

Since pimozide did considerably enhance accumulation of ethidium bromide in a fluorescence assay, ethidium bromide MIC assays in the presence and absence of this putative EPI were performed. They revealed that pimozide was able to reduce the MICs of ethidium bromide by 4-fold. In line with previous reports we suggest that the capability of EPIs to restore the susceptibility to antimicrobial agents can be highly substrate-specific due to different substrate binding sites.

Keywords: AcrB, efflux pump inhibitor, multidrug resistance, pimozide. .