JAC Advance Access originally published online on December 12, 2002
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Journal of Antimicrobial Chemotherapy (2003) 51, 13-17
© 2003 The British Society for Antimicrobial Chemotherapy
A novel inhibitor of multidrug efflux pumps in Staphylococcus aureus
1 Centre for Pharmacognosy and Phytotherapy, The School of Pharmacy, University of London, 29–39 Brunswick Square, London WC1N 1AX, UK; 2 Division of Infectious Diseases, Department of Internal Medicine, School of Medicine, Wayne State University and the John D. Dingell Department of Veterans Affairs Medical Center, Detroit, MI 48201, USA
Received 16 September 2002; returned 8 October 2002; revised 11 October 2002; accepted 15 October 2002
GG918, a synthetic inhibitor of P-glycoprotein-mediated mammalian tumour multidrug resistance, was found to be equipotent to reserpine in enhancing the in vitro activity of norfloxacin and ciprofloxacin against strains of Staphylococcus aureus expressing distinct efflux-related multidrug resistance pumps. Four- to eight-fold reductions in MICs of these fluoroquinolones were observed for SA-1199B, a strain that overexpresses NorA (the major S. aureus multidrug transporter), and SA-K2068, which possesses a multidrug efflux-related pump distinct from NorA. Neither inhibitor potentiated the activity of newer fluoroquinolones such as levofloxacin or moxifloxacin by more than two-fold, and this effect was observed only in SA-1199B and SA-K2068. GG918 and reserpine exposure resulted in two- to four-fold reductions in norfloxacin and ciprofloxacin MICs in a fluoroquinolone-susceptible control strain and in strains expressing the MsrA and TetK proteins, which mediate efflux-related resistance to macrolides and tetracyclines, respectively, suggesting inhibition of as yet uncharacterized pumps for which norfloxacin and ciprofloxacin are substrates. In the MsrA- and TetK-expressing strains no more than a two-fold augmentation of erythromycin or tetracycline activity was observed with either inhibitor, suggesting minimal, if any, inhibitory activity against these efflux proteins. Using GG918 as a lead compound, a structure–activity evaluation may reveal a more potent and broader spectrum inhibitor of S. aureus antibiotic efflux pumps.
Keywords: multidrug efflux, GG918, Staphylococcus aureus
* Corresponding author. Tel: +44-20-7753-5913; Fax: +44-20-7753-5909; E-mail: simon.gibbons{at}ulsop.ac.uk
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