A novel inhibitor of multidrug efflux pumps in Staphylococcus aureus

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.