title: Cardiolipin prevents membrane translocation and permeabilization by daptomycin.
abstract: Daptomycin is an acidic lipopeptide antibiotic that, in the presence of calcium, forms oligomeric pores on membranes containing phosphatidylglycerol. It is clinically used against various Gram-positive bacteria such as Staphylococcus aureus and Enterococcus species. Genetic studies have indicated that an increased content of cardiolipin in the bacterial membrane may contribute to bacterial resistance against the drug. Here, we used a liposome model to demonstrate that cardiolipin directly inhibits membrane permeabilization by daptomycin. When cardiolipin is added at molar fractions of 10 or 20% to membranes containing phosphatidylglycerol, daptomycin no longer forms pores or translocates to the inner membrane leaflet. Under the same conditions, daptomycin continues to form oligomers; however, these oligomers contain only close to four subunits, which is approximately half as many as observed on membranes without cardiolipin. The collective findings lead us to propose that a daptomycin pore consists of two aligned tetramers in opposite leaflets and that cardiolipin prevents the translocation of tetramers to the inner leaflet, thereby forestalling the formation of complete, octameric pores. Our findings suggest a possible mechanism by which cardiolipin may mediate resistance to daptomycin, and they provide new insights into the action mode of this important antibiotic.
authors.affiliation: Department of Chemistry, University of Waterloo, Waterloo, Ontario N2L3G1, Canada.
authors.forename: TianHua
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, University of Al-Muthanna, Samawah, Al-Muthanna, Iraq.
authors.forename: Jawad K
authors.initials: JK
authors.lastname: Muraih
authors.affiliation: Department of Chemistry and Biochemistry, Stern College for Women, Yeshiva University, New York, New York 10033.
authors.forename: Nasim
authors.initials: N
authors.lastname: Tishbi
authors.affiliation: Department of Chemistry and Biochemistry, Stern College for Women, Yeshiva University, New York, New York 10033.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Herskowitz
authors.affiliation: Department of Chemistry and Biochemistry, Stern College for Women, Yeshiva University, New York, New York 10033.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Victor
authors.affiliation: Cubist Pharmaceuticals Inc., Lexington, Massachusetts 02421.
authors.forename: Jared
authors.initials: J
authors.lastname: Silverman
authors.affiliation: Department of Chemistry, University of Waterloo, Waterloo, Ontario N2L3G1, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Uwumarenogie
authors.affiliation: Department of Chemistry, University of Waterloo, Waterloo, Ontario N2L3G1, Canada.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Taylor
authors.affiliation: Department of Chemistry, University of Waterloo, Waterloo, Ontario N2L3G1, Canada. Electronic address: mpalmer@uwaterloo.ca.
authors.forename: Michael
authors.initials: M
authors.lastname: Palmer
authors.affiliation: Department of Chemistry and Biochemistry, Stern College for Women, Yeshiva University, New York, New York 10033.
authors.forename: Evan
authors.initials: E
authors.lastname: Mintzer
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects* / Q000502:physiology; D002151:Calorimetry; D002308:Cardiolipins / Q000502:physiology*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D017576:Daptomycin / Q000494:pharmacology*; D006094:Gram-Positive Bacteria / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D002308:Cardiolipins; D017576:Daptomycin
keywords: Antibiotic Resistance; Antibiotics Action; Cardiolipin; Fluorescence; Isothermal Titration Calorimetry; Langmuir Monolayers; Lipopeptides; Liposomes; Phosphatidylglycerol