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Antimicrobial Agents and Chemotherapy, August 2003, p. 2538-2544, Vol. 47, No. 8
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.8.2538-2544.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Correlation of Daptomycin Bactericidal Activity and Membrane Depolarization in Staphylococcus aureus

Jared A. Silverman,1* Nancy G. Perlmutter,2 and Howard M. Shapiro2

Cubist Pharmaceuticals, Inc., Lexington,1 Howard M. Shapiro, M. D., P. C., West Newton, Massachusetts2

Received 23 December 2002/ Returned for modification 17 March 2003/ Accepted 7 May 2003

The objective of this study was to further elucidate the role of membrane potential in the mechanism of action of daptomycin, a novel lipopeptide antibiotic. Membrane depolarization was measured by both fluorimetric and flow cytometric assays. Adding daptomycin (5 µg/ml) to Staphylococcus aureus gradually dissipated membrane potential. In both assays, cell viability was reduced by >99% and membrane potential was reduced by >90% within 30 min of adding daptomycin. Cell viability decreased in parallel with changes in membrane potential, demonstrating a temporal correlation between bactericidal activity and membrane depolarization. Decreases in viability and potential also showed a dose-dependent correlation. Depolarization is indicative of ion movement across the cytoplasmic membrane. Fluorescent probes were used to demonstrate Ca2+-dependent, daptomycin-triggered potassium release from S. aureus. Potassium release was also correlated with bactericidal activity. This study demonstrates a clear correlation between dissipation of membrane potential and the bactericidal activity of daptomycin. A multistep model for daptomycin's mechanism of action is proposed.

* Corresponding author. Mailing address: Cubist Pharmaceuticals, Inc., 65 Hayden Ave., Lexington, MA 02421. Phone: (781) 860-8405. Fax: (781) 861-1164. E-mail: jared.silverman{at}cubist.com.

Antimicrobial Agents and Chemotherapy, August 2003, p. 2538-2544, Vol. 47, No. 8
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.8.2538-2544.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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