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PMID: 12878516 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Correlation of daptomycin bactericidal activity and membrane depolarization in Staphylococcus aureus.

Antimicrobial agents and chemotherapy ·Vol. 47 ·No. 8 ·2003-08-00 ·Pages 2538-44

Silverman JA, Perlmutter NG, Shapiro HM

Abstract

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 micro g/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 Ca(2+)-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.

MeSH Terms
Anti-Bacterial Agents/pharmacology Cell Membrane/drug effects,metabolism Culture Media Daptomycin/pharmacology Dose-Response Relationship, Drug Flow Cytometry Fluorometry Membrane Potentials/drug effects Potassium/metabolism Staphylococcus aureus/drug effects,metabolism
Chemicals
Anti-Bacterial Agents Culture Media Daptomycin Potassium
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Silverman Jared A
Cubist Pharmaceuticals, Inc., Lexington, Massachusetts 02421, USA. jared.silverman@cubist.com
Perlmutter Nancy G
Shapiro Howard M
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Article Info
Journal
Antimicrobial agents and chemotherapy
Abbr.
Antimicrob Agents Chemother
ISSN
0066-4804
DOI
10.1128/AAC.47.8.2538-2544.2003
Email
jared.silverman@cubist.com
Published
2003-08-00
Pages
2538-44
Language
English
Region
United States
NLM ID
0315061
PMCID
PMC166110
Subset
IM
Grants
NIAID NIH HHS · AI48354 · United States
External Links
PubMed source DOI: 10.1128/AAC.47.8.2538-2544.2003 PMC Full Text View journal details
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