Daptomycin Leakage Is Selective.
Daptomycin is a lipopeptide antibiotic approved for use against Gram-positive organisms, including highly resistant species. A number of studies have suggested that daptomycin kills bacteria by membrane permeabilization and depolarization. Recently a model membrane system consisting of 1,2-dimyristoyl-sn-glycero-3-phosphocholine and 1,2-dimyristoyl-sn-glycero-3-phospho-(1'-rac-glycerol) in a 1:1 ratio and the ionophore CCCP was proposed as a simple model to investigate the mode of action of daptomycin and resistance mechanisms at a molecular level. This study investigates how this model depends on the composition of the membrane and the role of CCCP. Results obtained from a fluorescence assay using pyranine show that daptomycin causes leakage in liposomes of limited stability and that CCCP promotes this leakage. A different model membrane system used here, which relies on ion selective dyes such as 4,4'-[1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diylbis(5-methoxy-6,2-benzofurandiyl)]bis-, tetrakis[(acetyloxy)methyl] ester (PBFI), and 4,4'-[1,4,10-trioxa-7,13-diazacyclopentadecane-7,13-diylbis(5-methoxy-6,2-benzofurandiyl)]bis-, tetraammonium salt (SBFI), is a more robust alternative. Findings based on this newer model suggest that daptomycin is selective for potassium.
Department of Chemistry, University of British Columbia , 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
Jin
J
Zhang
Department of Chemistry, University of British Columbia , 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
Kyle
K
Scoten
Department of Chemistry, University of British Columbia , 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
Suzana K
SK
Straus
D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D017576:Daptomycin / Q000378:metabolism* / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D012964:Sodium / Q000378:metabolism
D000900:Anti-Bacterial Agents; D012964:Sodium; D017576:Daptomycin; D011188:Potassium
1,3-benzenedicarboxylic acid; 4,4′-[1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diylbis(5-methoxy-6,2-benzofurandiyl)]bis-, tetrakis[(acetyloxy)methyl] ester (PBFI); 4,4′-[1,4,10-trioxa-7,13-diazacyclopentadecane-7,13-diylbis(5-methoxy-6,2-benzofurandiyl)]bis-, tetraammonium salt (SBFI); carbonyl cyanide m-chlorophenyl hydrazine (CCCP); daptomycin; fluorescence; leakage; lipopeptide; membrane depolarization; pyranine