This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Silverman, J. A.
Right arrow Articles by Shapiro, H. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Silverman, J. A.
Right arrow Articles by Shapiro, H. M.

 Previous Article  |  Next Article 

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.



This article has been cited by other articles:

  • Steenbergen, J. N., Mohr, J. F., Thorne, G. M. (2009). Effects of daptomycin in combination with other antimicrobial agents: a review of in vitro and animal model studies. J Antimicrob Chemother 64: 1130-1138 [Abstract] [Full Text]  
  • Leung, K.-P., Abercrombie, J.J., Campbell, T.M., Gilmore, K.D., Bell, C.A., Faraj, J.A., DeLuca, P.P. (2009). Antimicrobial Peptides for Plaque Control. ADR 21: 57-62 [Full Text]  
  • John, A.-K., Baldoni, D., Haschke, M., Rentsch, K., Schaerli, P., Zimmerli, W., Trampuz, A. (2009). Efficacy of Daptomycin in Implant-Associated Infection Due to Methicillin-Resistant Staphylococcus aureus: Importance of Combination with Rifampin. Antimicrob. Agents Chemother. 53: 2719-2724 [Abstract] [Full Text]  
  • Mishra, N. N., Yang, S.-J., Sawa, A., Rubio, A., Nast, C. C., Yeaman, M. R., Bayer, A. S. (2009). Analysis of Cell Membrane Characteristics of In Vitro-Selected Daptomycin-Resistant Strains of Methicillin-Resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 53: 2312-2318 [Abstract] [Full Text]  
  • Hachmann, A.-B., Angert, E. R., Helmann, J. D. (2009). Genetic Analysis of Factors Affecting Susceptibility of Bacillus subtilis to Daptomycin. Antimicrob. Agents Chemother. 53: 1598-1609 [Abstract] [Full Text]  
  • Wecke, T., Zuhlke, D., Mader, U., Jordan, S., Voigt, B., Pelzer, S., Labischinski, H., Homuth, G., Hecker, M., Mascher, T. (2009). Daptomycin versus Friulimicin B: In-Depth Profiling of Bacillus subtilis Cell Envelope Stress Responses. Antimicrob. Agents Chemother. 53: 1619-1623 [Abstract] [Full Text]  
  • Schneider, T., Gries, K., Josten, M., Wiedemann, I., Pelzer, S., Labischinski, H., Sahl, H.-G. (2009). The Lipopeptide Antibiotic Friulimicin B Inhibits Cell Wall Biosynthesis through Complex Formation with Bactoprenol Phosphate. Antimicrob. Agents Chemother. 53: 1610-1618 [Abstract] [Full Text]  
  • Belley, A., Neesham-Grenon, E., McKay, G., Arhin, F. F., Harris, R., Beveridge, T., Parr, T. R. Jr., Moeck, G. (2009). Oritavancin Kills Stationary-Phase and Biofilm Staphylococcus aureus Cells In Vitro. Antimicrob. Agents Chemother. 53: 918-925 [Abstract] [Full Text]  
  • Kirby, A., Mohandas, K., Broughton, C., Neal, T. J., Smith, G. W., Pai, P., Nistal de Paz, C. (2009). In vivo development of heterogeneous glycopeptide-intermediate Staphylococcus aureus (hGISA), GISA and daptomycin resistance in a patient with meticillin-resistant S. aureus endocarditis. J Med Microbiol 58: 376-380 [Abstract] [Full Text]  
  • Camargo, I. L. B. d. C., Neoh, H.-M., Cui, L., Hiramatsu, K. (2008). Serial Daptomycin Selection Generates Daptomycin-Nonsusceptible Staphylococcus aureus Strains with a Heterogeneous Vancomycin-Intermediate Phenotype. Antimicrob. Agents Chemother. 52: 4289-4299 [Abstract] [Full Text]  
  • Hobbs, J. K., Miller, K., O'Neill, A. J., Chopra, I. (2008). Consequences of daptomycin-mediated membrane damage in Staphylococcus aureus. J Antimicrob Chemother 62: 1003-1008 [Abstract] [Full Text]  
  • Hawkey, P. M. (2008). Pre-clinical experience with daptomycin. J Antimicrob Chemother 62: iii7-iii14 [Abstract] [Full Text]  
  • Murthy, M. H., Olson, M. E., Wickert, R. W., Fey, P. D., Jalali, Z. (2008). Daptomycin non-susceptible meticillin-resistant Staphylococcus aureus USA 300 isolate. J Med Microbiol 57: 1036-1038 [Abstract] [Full Text]  
  • Cotroneo, N., Harris, R., Perlmutter, N., Beveridge, T., Silverman, J. A. (2008). Daptomycin Exerts Bactericidal Activity without Lysis of Staphylococcus aureus. Antimicrob. Agents Chemother. 52: 2223-2225 [Abstract] [Full Text]  
  • Rose, W. E., Leonard, S. N., Sakoulas, G., Kaatz, G. W., Zervos, M. J., Sheth, A., Carpenter, C. F., Rybak, M. J. (2008). Daptomycin Activity against Staphylococcus aureus following Vancomycin Exposure in an In Vitro Pharmacodynamic Model with Simulated Endocardial Vegetations. Antimicrob. Agents Chemother. 52: 831-836 [Abstract] [Full Text]  
  • Muthaiyan, A., Silverman, J. A., Jayaswal, R. K., Wilkinson, B. J. (2008). Transcriptional Profiling Reveals that Daptomycin Induces the Staphylococcus aureus Cell Wall Stress Stimulon and Genes Responsive to Membrane Depolarization. Antimicrob. Agents Chemother. 52: 980-990 [Abstract] [Full Text]  
  • Ponticelli, C. (2008). New recommendations in the treatment of Gram-positive bacteraemia in dialysis patients. Nephrol Dial Transplant 23: 27-32 [Full Text]  
  • Jones, T., Yeaman, M. R., Sakoulas, G., Yang, S.-J., Proctor, R. A., Sahl, H.-G., Schrenzel, J., Xiong, Y. Q., Bayer, A. S. (2008). Failures in Clinical Treatment of Staphylococcus aureus Infection with Daptomycin Are Associated with Alterations in Surface Charge, Membrane Phospholipid Asymmetry, and Drug Binding. Antimicrob. Agents Chemother. 52: 269-278 [Abstract] [Full Text]  
  • Mascio, C. T. M., Alder, J. D., Silverman, J. A. (2007). Bactericidal Action of Daptomycin against Stationary-Phase and Nondividing Staphylococcus aureus Cells. Antimicrob. Agents Chemother. 51: 4255-4260 [Abstract] [Full Text]  
  • LaPlante, K. L., Mermel, L. A. (2007). In vitro activity of daptomycin and vancomycin lock solutions on staphylococcal biofilms in a central venous catheter model. Nephrol Dial Transplant 22: 2239-2246 [Abstract] [Full Text]  
  • Falagas, M. E., Giannopoulou, K. P., Ntziora, F., Vardakas, K. Z. (2007). Daptomycin for endocarditis and/or bacteraemia: a systematic review of the experimental and clinical evidence. J Antimicrob Chemother 60: 7-19 [Abstract] [Full Text]  
  • Grandgirard, D., Schurch, C., Cottagnoud, P., Leib, S. L. (2007). Prevention of Brain Injury by the Nonbacteriolytic Antibiotic Daptomycin in Experimental Pneumococcal Meningitis. Antimicrob. Agents Chemother. 51: 2173-2178 [Abstract] [Full Text]  
  • Benvenuto, M., Benziger, D. P., Yankelev, S., Vigliani, G. (2006). Pharmacokinetics and Tolerability of Daptomycin at Doses up to 12 Milligrams per Kilogram of Body Weight Once Daily in Healthy Volunteers.. Antimicrob. Agents Chemother. 50: 3245-3249 [Abstract] [Full Text]  
  • Friedman, L., Alder, J. D., Silverman, J. A. (2006). Genetic Changes That Correlate with Reduced Susceptibility to Daptomycin in Staphylococcus aureus.. Antimicrob. Agents Chemother. 50: 2137-2145 [Abstract] [Full Text]  
  • Huang, V., Rybak, M. J. (2006). Evaluation of daptomycin activity against Staphylococcus aureus in an in vitro pharmacodynamic model under normal and simulated impaired renal function. J Antimicrob Chemother 57: 116-121 [Abstract] [Full Text]  
  • Heinzelmann, E., Berger, S., Muller, C., Hartner, T., Poralla, K., Wohlleben, W., Schwartz, D. (2005). An acyl-CoA dehydrogenase is involved in the formation of the {Delta}cis3 double bond in the acyl residue of the lipopeptide antibiotic friulimicin in Actinoplanes friuliensis. Microbiology 151: 1963-1974 [Abstract] [Full Text]  
  • Schriever, C. A., Fernandez, C., Rodvold, K. A., Danziger, L. H. (2005). Daptomycin: A novel cyclic lipopeptide antimicrobial. Am J Health Syst Pharm 62: 1145-1158 [Abstract] [Full Text]  
  • Streit, J. M., Steenbergen, J. N., Thorne, G. M., Alder, J., Jones, R. N. (2005). Daptomycin tested against 915 bloodstream isolates of viridans group streptococci (eight species) and Streptococcus bovis. J Antimicrob Chemother 55: 574-578 [Abstract] [Full Text]  
  • Higgins, D. L., Chang, R., Debabov, D. V., Leung, J., Wu, T., Krause, K. M., Sandvik, E., Hubbard, J. M., Kaniga, K., Schmidt, D. E. Jr., Gao, Q., Cass, R. T., Karr, D. E., Benton, B. M., Humphrey, P. P. (2005). Telavancin, a Multifunctional Lipoglycopeptide, Disrupts both Cell Wall Synthesis and Cell Membrane Integrity in Methicillin-Resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 49: 1127-1134 [Abstract] [Full Text]  
  • Steenbergen, J. N., Alder, J., Thorne, G. M., Tally, F. P. (2005). Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections. J Antimicrob Chemother 55: 283-288 [Abstract] [Full Text]  
  • Lipsky, B. A., Stoutenburgh, U. (2005). Daptomycin for treating infected diabetic foot ulcers: evidence from a randomized, controlled trial comparing daptomycin with vancomycin or semi-synthetic penicillins for complicated skin and skin-structure infections. J Antimicrob Chemother 55: 240-245 [Abstract] [Full Text]  
  • Rand, K. H., Houck, H. J. (2004). Synergy of Daptomycin with Oxacillin and Other {beta}-Lactams against Methicillin-Resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 48: 2871-2875 [Abstract] [Full Text]  
  • Streit, J. M., Jones, R. N., Sader, H. S. (2004). Daptomycin activity and spectrum: a worldwide sample of 6737 clinical Gram-positive organisms. J Antimicrob Chemother 53: 669-674 [Abstract] [Full Text]  
  • Rand, K. H., Houck, H. (2004). Daptomycin synergy with rifampicin and ampicillin against vancomycin-resistant enterococci. J Antimicrob Chemother 53: 530-532 [Abstract] [Full Text]  
  • Laganas, V., Alder, J., Silverman, J. A. (2003). In Vitro Bactericidal Activities of Daptomycin against Staphylococcus aureus and Enterococcus faecalis Are Not Mediated by Inhibition of Lipoteichoic Acid Biosynthesis. Antimicrob. Agents Chemother. 47: 2682-2684 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»