Multiple novel inhibitors of the NorA multidrug transporter of Staphylococcus aureus

The multidrug transporter NorA contributes to the resistance of Staphylococ cus aureus to fluoroquinolone antibiotics by promoting their active extrusi on from the cell. Previous studies with the alkaloid reserpine, the first i dentified inhibitor of NorA, indicate that the combination of a chemical No rA inhibitor with a fluoroquinolone could improve the efficacy of this clas s of antibiotics, Since reserpine is toxic to humans at the concentrations required to inhibit NorA, we sought to identify new inhibitors of Nord that may be used in a clinical setting. Screening of a chemical library yielded a number of structurally diverse inhibitors of NorA that were more potent than reserpine. The new inhibitors act in a synergistic manner with the mos t widely used fluoroquinolone, ciprofloxacin, by substantially increasing i ts activity against both NorA-overexpressing and wild-type S. aureus isolat es. Furthermore, the inhibitors dramatically suppress the emergence of cipr ofloxacin-resistant S. aureus upon in vitro selection with this drug, Some of these new inhibitors, or their derivatives, may prove useful for augment ation of the antibacterial activities of fluoroquinolones in the clinical s etting.