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Antimicrobial Agents and Chemotherapy, February 2003, p. 719-726, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.719-726.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Phenothiazines and Thioxanthenes Inhibit Multidrug Efflux Pump Activity in Staphylococcus aureus

Glenn W. Kaatz,1,2* Varsha V. Moudgal,2 Susan M. Seo,2 and Jette E. Kristiansen3

The John D. Dingell Department of Veteran's Affairs Medical Center,1 Department of Internal Medicine, Division of Infectious Diseases, Wayne State University School of Medicine, Detroit, Michigan 48201,2 Department of Clinical Microbiology, Sonderborg Sygehus, Sonderborg, Denmark3

Received 10 June 2002/ Returned for modification 8 September 2002/ Accepted 15 November 2002

Efflux-related multidrug resistance (MDR) is a significant means by which bacteria can evade the effects of selected antimicrobial agents. Genome sequencing data suggest that Staphylococcus aureus may possess numerous chromosomally encoded MDR efflux pumps, most of which have not been characterized. Inhibition of these pumps, which may restore clinically relevant activity of antimicrobial agents that are substrates for them, may be an effective alternative to the search for new antimicrobial agents that are not substrates. The inhibitory effects of selected phenothiazines and two geometric stereoisomers of the thioxanthene flupentixol were studied using strains of S. aureus possessing unique efflux-related MDR phenotypes. These compounds had some intrinsic antimicrobial activity and, when combined with common MDR efflux pump substrates, resulted in additive or synergistic interactions. For S. aureus SA-1199B, which overexpresses the NorA MDR efflux pump, and for two additional strains of S. aureus having non-NorA-mediated MDR phenotypes, the 50% inhibitory concentration (IC50) for ethidium efflux for all tested compounds was between 4 and 15% of their respective MICs. Transport of other substrates was less susceptible to inhibition; the prochlorperazine IC50 for acriflavine and pyronin Y efflux by SA-1199B was more than 60% of its MIC. Prochlorperazine and trans(E)-flupentixol were found to reduce the proton motive force (PMF) of S. aureus by way of a reduction in the transmembrane potential. We conclude that the mechanism by which phenothiazines and thioxanthenes inhibit efflux by PMF-dependent pumps is multifactorial and, because of the unbalanced effect of these compounds on the MICs and the efflux of different substrates, may involve an interaction with the pump itself and, to a lesser extent, a reduction in the transmembrane potential.

* Corresponding author. Mailing address: Department of Internal Medicine, Division of Infectious Diseases, Wayne State University School of Medicine, B4333 John D. Dingell VA Medical Center, 4646 John R, Detroit, MI 48201. Phone: (313) 576-4487. Fax: (313) 576-1112. E-mail: gkaatz{at}juno.com.

Antimicrobial Agents and Chemotherapy, February 2003, p. 719-726, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.719-726.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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