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Daptomycin forms cation- and size-selective pores in model membranes

TianHua Zhang1, Jawad K Muraih2, Ben MacCormick3

  • 1Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada.

Biochimica Et Biophysica Acta
|May 27, 2014
PubMed

Insights

Daptomycin forms calcium-dependent pores in bacterial membranes. These pores are selective for cations like sodium and potassium, explaining how daptomycin depolarizes and kills Gram-positive bacteria.

Area of Science:

  • Microbiology
  • Biochemistry
  • Pharmacology

Background:

  • Daptomycin is a critical lipopeptide antibiotic for treating severe Gram-positive bacterial infections.
  • Its mechanism involves calcium-dependent membrane binding and oligomerization, leading to bacterial cell death.
  • Observed bacterial membrane depolarization suggests daptomycin forms pores.

Purpose of the Study:

  • To characterize the permeability properties of daptomycin-induced pores using a liposome model.
  • To elucidate the specific ion selectivity of these daptomycin pores.

Main Methods:

  • Utilized a liposome model system to investigate daptomycin pore formation.
  • Assessed the permeability of various ions, including cations and anions, through these pores.

Main Results:

  • Daptomycin pores are selective for cations, with highest permeability for alkali metal ions (Na+, K+).
  • Permeability is reduced for divalent cations (Mg++) and organic cations (choline, hexamethonium).
  • Anions and zwitterions like cysteine are excluded from the pores.

Conclusions:

  • The characterized daptomycin pores explain the observed bacterial membrane depolarization.
  • Sodium influx through these selective cation pores is the primary driver of depolarization in vivo.
  • Findings provide insight into the molecular mechanism of daptomycin's bactericidal activity.
Keywords:
AptomycinFluorescenceLipopeptideMembrane permeabilizationPore-formationPyranine

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