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Antimicrobial Agents and Chemotherapy, October 1999, p. 2404-2408, Vol. 43, No. 10
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Multiple Novel Inhibitors of the NorA Multidrug Transporter of Staphylococcus aureus

Penelope N. Markham,1,* Eric Westhaus,1 Katya Klyachko,2 Michael E. Johnson,2 and Alex A. Neyfakh2

Influx, Inc., Chicago, Illinois 60612,1 and Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, Illinois 606072

Received 21 May 1999/Returned for modification 29 June 1999/Accepted 2 August 1999

The multidrug transporter NorA contributes to the resistance of Staphylococcus aureus to fluoroquinolone antibiotics by promoting their active extrusion from the cell. Previous studies with the alkaloid reserpine, the first identified inhibitor of NorA, indicate that the combination of a chemical NorA inhibitor with a fluoroquinolone could improve the efficacy of this class of antibiotics. Since reserpine is toxic to humans at the concentrations required to inhibit NorA, we sought to identify new inhibitors of NorA 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 most widely used fluoroquinolone, ciprofloxacin, by substantially increasing its activity against both NorA-overexpressing and wild-type S. aureus isolates. Furthermore, the inhibitors dramatically suppress the emergence of ciprofloxacin-resistant S. aureus upon in vitro selection with this drug. Some of these new inhibitors, or their derivatives, may prove useful for augmentation of the antibacterial activities of fluoroquinolones in the clinical setting.

* Corresponding author. Mailing address: Influx, Inc., 2201 West Campbell Park Dr., Chicago, IL 60612. Phone and Fax: (312) 492-7760. E-mail: pmarkham{at}uic.edu.

Antimicrobial Agents and Chemotherapy, October 1999, p. 2404-2408, Vol. 43, No. 10
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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