JAC Advance Access published online on December 12, 2002
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkg044
© 2002 by The British Society for Antimicrobial Chemotherapy
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Original Paper
1 Centre for Pharmacognosy
and Phytotherapy, The School of Pharmacy, University of London,
29-39 Brunswick Square, London WC1N 1AX, UK
* Corresponding author. E-mail: simon.gibbons{at}ulsop.ac.uk.
Received 16 September 2002
; revised 8 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
A novel inhibitor of multidrug efflux pumps in Staphylococcus aureus
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
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