title: Interaction of daptomycin with lipid bilayers: a lipid extracting effect.
abstract: Daptomycin is the first approved member of a new structural class of antibiotics, the cyclic lipopeptides. The peptide interacts with the lipid matrix of cell membranes, inducing permeability of the membrane to ions, but its molecular mechanism has been a puzzle. Unlike the ubiquitous membrane-acting host-defense antimicrobial peptides, daptomycin does not induce pores in the cell membranes. Thus, how it affects the permeability of a membrane to ions is not clear. We studied its interaction with giant unilamellar vesicles (GUVs) and discovered a lipid-extracting phenomenon that correlates with the direct action of daptomycin on bacterial membranes observed in a recent fluorescence microscopy study. Lipid extraction occurred only when the GUV lipid composition included phosphatidylglycerol and in the presence of Ca(2+) ions, the same condition found to be necessary for daptomycin to be effective against bacteria. Furthermore, it occurred only when the peptide/lipid ratio exceeded a threshold value, which could be the basis of the minimal inhibitory concentration of daptomycin. In this first publication on the lipid extracting effect, we characterize its dependence on ions and lipid compositions. We also discuss possibilities for connecting the lipid extracting effect to the antibacterial activity of daptomycin.
authors.affiliation: Department of Physics and Astronomy, Rice University , Houston, Texas 77005, United States.
authors.forename: Yen-Fei
authors.initials: YF
authors.lastname: Chen
authors.forename: Tzu-Lin
authors.initials: TL
authors.lastname: Sun
authors.forename: Yen
authors.initials: Y
authors.lastname: Sun
authors.forename: Huey W
authors.initials: HW
authors.lastname: Huang
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry; D001896:Boron Compounds / Q000737:chemistry; D002118:Calcium / Q000737:chemistry; D002308:Cardiolipins / Q000737:chemistry; D017576:Daptomycin / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry*; D008239:Lysine / Q000737:chemistry; D010715:Phosphatidylglycerols / Q000737:chemistry; D053835:Unilamellar Liposomes / Q000737:chemistry / Q000378:metabolism
chemical_list: C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D000900:Anti-Bacterial Agents; D001896:Boron Compounds; D002308:Cardiolipins; D008051:Lipid Bilayers; D010715:Phosphatidylglycerols; D053835:Unilamellar Liposomes; C002285:lysylphosphatidylglycerol; D008239:Lysine; D017576:Daptomycin; D002118:Calcium
references.citation: Swiss Med Wkly. 2008 Feb 23;138(7-8):93-9
references.pmid: 18293118
references.citation: Biochim Biophys Acta. 2011 Apr;1808(4):1154-60
references.pmid: 21223947
references.citation: Biophys J. 2010 Jul 21;99(2):544-52
references.pmid: 20643073
references.citation: Biophys J. 2001 Sep;81(3):1475-85
references.pmid: 11509361
references.citation: Diagn Microbiol Infect Dis. 2000 Sep;38(1):51-8
references.pmid: 11025184
references.citation: FEBS J. 2006 Aug;273(15):3614-24
references.pmid: 16884500
references.citation: Biochim Biophys Acta. 2012 Jul;1818(7):1642-7
references.pmid: 22387459
references.citation: Antimicrob Agents Chemother. 2013 Jan;57(1):289-96
references.pmid: 23114777
references.citation: Nature. 2002 Jan 24;415(6870):389-95
references.pmid: 11807545
references.citation: J Am Chem Soc. 2009 Feb 11;131(5):1706-16
references.pmid: 19146415
references.citation: Biophys J. 2012 Mar 7;102(5):1059-68
references.pmid: 22404928
references.citation: Biopolymers. 2005;80(2-3):374-85
references.pmid: 15815985
references.citation: Diabetes. 1999 Mar;48(3):491-8
references.pmid: 10078548
references.citation: Biochemistry. 2000 Jul 25;39(29):8347-52
references.pmid: 10913240
references.citation: Proc Natl Acad Sci U S A. 2008 Nov 11;105(45):17379-83
references.pmid: 18987313
references.citation: Eur Biophys J. 2008 Apr;37(4):421-33
references.pmid: 17968536
references.citation: J Bacteriol. 1975 Jul;123(1):187-95
references.pmid: 1095550
references.citation: J Biol Chem. 2000 May 12;275(19):14077-83
references.pmid: 10799482
references.citation: Chem Biol. 2004 Jul;11(7):949-57
references.pmid: 15271353
references.citation: Antimicrob Agents Chemother. 2001 Jun;45(6):1919-22
references.pmid: 11353654
references.citation: Biochim Biophys Acta. 2013 Feb;1828(2):223-32
references.pmid: 23085001
references.citation: N Engl J Med. 2011 Sep 8;365(10):892-900
references.pmid: 21899450
references.citation: Antimicrob Agents Chemother. 2011 Sep;55(9):4326-37
references.pmid: 21709092
references.citation: Org Biomol Chem. 2004 Jul 7;2(13):1872-8
references.pmid: 15227539
references.citation: Science. 1993 Sep 17;261(5128):1558-60
references.pmid: 17798113
references.citation: Biochemistry. 1996 Oct 29;35(43):13723-8
references.pmid: 8901513
references.citation: Biochim Biophys Acta. 1998 Nov 10;1376(3):391-400
references.pmid: 9804997
references.citation: Proc Natl Acad Sci U S A. 2013 Aug 27;110(35):14243-8
references.pmid: 23940362
references.citation: Biochim Biophys Acta. 2006 Sep;1758(9):1215-23
references.pmid: 16615993
references.citation: Antimicrob Agents Chemother. 2011 Jul;55(7):3345-56
references.pmid: 21502617
references.citation: Antimicrob Agents Chemother. 2008 Jan;52(1):269-78
references.pmid: 17954690
references.citation: Antimicrob Agents Chemother. 2007 Dec;51(12):4255-60
references.pmid: 17923487
references.citation: J Phys Chem B. 2006 Oct 26;110(42):21327-37
references.pmid: 17048962
references.citation: Biophys J. 1981 Sep;35(3):637-52
references.pmid: 7272454
references.citation: Biophys J. 2007 Mar 15;92(6):1878-90
references.pmid: 17208976
references.citation: J Antimicrob Chemother. 2008 Nov;62(5):1003-8
references.pmid: 18669516
references.citation: Endocr Rev. 2008 May;29(3):303-16
references.pmid: 18314421
references.citation: J Biol Chem. 2014 Apr 25;289(17):11584-11591
references.pmid: 24616102
references.citation: Biophys J. 2009 Feb;96(3):1026-35
references.pmid: 19186140
references.citation: J Biol Chem. 1977 Aug 25;252(16):5875-82
references.pmid: 18476
references.citation: Biochim Biophys Acta. 1999 Dec 15;1462(1-2):55-70
references.pmid: 10590302
references.citation: J Biol Chem. 2004 Nov 5;279(45):46363-6
references.pmid: 15385542
references.citation: mBio. 2013 Jul 23;4(4):
references.pmid: 23882013
references.citation: Cell. 1993 Jun 18;73(6):1055-8
references.pmid: 8513491
references.citation: Chem Phys Lipids. 2008 Aug;154(2):120-8
references.pmid: 18489906
references.citation: Biophys J. 2010 May 19;98(10):2236-45
references.pmid: 20483332
references.citation: Biochim Biophys Acta. 2012 Mar;1818(3):673-8
references.pmid: 22079564
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10427-32
references.pmid: 16020533
references.citation: Chem Biol Drug Des. 2013 Aug;82(2):167-77
references.pmid: 23581817
references.citation: Antimicrob Agents Chemother. 2003 Aug;47(8):2538-44
references.pmid: 12878516
references.citation: Biochim Biophys Acta. 2014 Oct;1838(10):2425-30
references.pmid: 24857935
references.citation: J Am Chem Soc. 2006 Sep 27;128(38):12462-7
references.pmid: 16984196
references.citation: Antimicrob Agents Chemother. 2008 Jun;52(6):2223-5
references.pmid: 18378708
references.citation: J Bacteriol. 2012 Sep;194(17):4494-504
references.pmid: 22661688
references.citation: J Biol Chem. 1996 Jan 26;271(4):1988-92
references.pmid: 8567648
references.citation: Biochemistry. 2002 Sep 24;41(38):11338-43
references.pmid: 12234175
references.citation: Proc Natl Acad Sci U S A. 2013 Apr 16;110(16):6382-7
references.pmid: 23576726
references.citation: J Antibiot (Tokyo). 1988 Aug;41(8):1093-105
references.pmid: 2844711
references.citation: Antimicrob Agents Chemother. 2009 Apr;53(4):1598-609
references.pmid: 19164152
references.citation: Mini Rev Med Chem. 2012 Mar;12(3):202-9
references.pmid: 22356191
references.citation: Antimicrob Agents Chemother. 2006 Jun;50(6):2137-45
references.pmid: 16723576
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5087-92
references.pmid: 18375755