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Antimicrobial Agents and Chemotherapy, December 2007, p. 4480-4483, Vol. 51, No. 12
0066-4804/07/$08.00+0     doi:10.1128/AAC.00216-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Phenolic Diterpene Totarol Inhibits Multidrug Efflux Pump Activity in Staphylococcus aureus{triangledown}

Eileen C. J. Smith,1 Glenn W. Kaatz,2,3 Susan M. Seo,3 Neale Wareham,4 Elizabeth M. Williamson,5 and Simon Gibbons1*

Centre for Pharmacognosy and Phytotherapy, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, United Kingdom,1 The John D. Dingell Department of Veteran's Affairs Medical Centre,2 Department of Internal Medicine, Division of Infectious Diseases, School of Medicine, Wayne State University, Detroit, Michigan 48201,3 Stiefel International R&D, Whitebrook Park, 68 Lower Cookham Road, Maidenhead, Berkshire SL6 8XY, United Kingdom,4 Department of Pharmacy, University of Reading, Whiteknights, Reading, Berks RG6 6AJ, United Kingdom5

Received 13 February 2007/ Returned for modification 23 March 2007/ Accepted 24 July 2007

The phenolic diterpene totarol had good antimicrobial activity against effluxing strains of Staphylococcus aureus. Subinhibitory concentrations reduced the MICs of selected antibiotics, suggesting that it may also be an efflux pump inhibitor (EPI). A totarol-resistant mutant that overexpressed norA was created to separate antimicrobial from efflux inhibitory activity. Totarol reduced ethidium efflux from this strain by 50% at 15 µM (1/4x MIC), and combination studies revealed marked reductions in ethidium MICs. These data suggest that totarol is a NorA EPI as well as an antistaphylococcal antimicrobial agent.

* Corresponding author. Mailing address: Centre for Pharmacognosy and Phytotherapy, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, United Kingdom. Phone: 44 207 7535913. Fax: 44 207 7535909. E-mail: simon.gibbons{at}pharmacy.ac.uk

{triangledown} Published ahead of print on 30 July 2007.

Antimicrobial Agents and Chemotherapy, December 2007, p. 4480-4483, Vol. 51, No. 12
0066-4804/07/$08.00+0     doi:10.1128/AAC.00216-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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