Probing the "charge cluster mechanism" in amphipathic helical cationic antimicrobial peptides.
Clustering of anionic lipids away from zwitterionic ones by cationic antimicrobial agents has recently been established as a mechanism of action of natural small, flexible peptides as well as non-natural synthetic peptide mimics. One of the largest classes of antimicrobial peptides consists of peptides that form cationic amphipathic helices on membranes and whose toxic action is dependent on the formation of pores in the membrane or through the "carpet" mechanism. We have evaluated the role of anionic lipid clustering for five of these peptides, i.e., MSI-78, MSI-103, MSI-469, MSI-843, and MSI-1254, with different sequences and properties. We determined whether these amphipathic helical cationic antimicrobial peptides cluster anionic lipids from zwitterionic ones and if this property is related to the species specificity of their toxicity. All five of these peptides were capable of lipid clustering, in contrast to the well-studied amphipathic helical antimicrobial peptide, magainin 2, which does not. We ascribe this difference to the lower density of positive charges in magainin 2. Peptides that efficiently cluster anionic lipids generally have a ratio of MIC for Staphylococcus aureus to that for Escherichia coli of >1. The addition of an N-terminal octyl chain did not preclude anionic charge clustering, although the ratio of MIC for S. aureus to that for E. coli was somewhat lowered. In most Gram-positive bacteria, there is a predominance of anionic lipids in the cytoplasmic membrane. In Gram-negative bacteria, however, clustering of anionic lipids away from zwitterionic ones is emerging as an important contributing mechanism of bacterial toxicity for some antimicrobial agents.
Epand
Raquel F
RF
Department of Biochemistry and Biomedical Sciences, McMaster University Health Sciences Centre, Hamilton, Ontario L8N 3Z5, Canada.
Maloy
W Lee
WL
Ramamoorthy
Ayyalusamy
A
Epand
Richard M
RM
D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002463:Cell Membrane Permeability; D004926:Escherichia coli / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D013211:Staphylococcus aureus / Q000378:metabolism
D023181:Antimicrobial Cationic Peptides; D010455:Peptides
Chemistry. 2009;15(9):2036-40
19180607
Biophys J. 2008 Oct;95(8):3872-81
18621832
Biophys J. 2009 Apr 22;96(8):3263-72
19383470
Biochem J. 2005 Jan 1;385(Pt 1):135-43
15344905
Biochim Biophys Acta. 2009 Aug;1788(8):1680-6
19010301
Curr Opin Pharmacol. 2009 Oct;9(5):571-6
19734091
Biopolymers. 2002 Sep;64(6):314-27
12124849
J Biol Chem. 2001 Jul 27;276(30):27899-906
11352918
Antimicrob Agents Chemother. 2009 Jun;53(6):2312-8
19332678
Biochim Biophys Acta. 1999 Dec 15;1462(1-2):11-28
10590300
Antimicrob Agents Chemother. 2009 Sep;53(9):3705-14
19581460
Biophys J. 2006 Jul 1;91(1):206-16
16603496
Biophys J. 2009 Oct 21;97(8):2250-7
19843457
Biophys Chem. 2007 Mar;126(1-3):197-200
16730877
Biochim Biophys Acta. 2009 Mar;1788(3):650-9
19118516
Mol Med. 2009 Jan-Feb;15(1-2):51-9
19015736
Biochim Biophys Acta. 2006 Sep;1758(9):1426-35
16616888
Biophys J. 2010 Mar 3;98(5):815-23
20197035
J Am Chem Soc. 2007 Feb 7;129(5):1022-3
17263370
Biochim Biophys Acta. 2007 Oct;1768(10):2500-9
17599802
Antimicrob Agents Chemother. 2005 Jan;49(1):269-75
15616305
World J Microbiol Biotechnol. 2007 Dec;23(12):1679-83
27517822
J Clin Invest. 1989 Aug;84(2):553-61
2668334
Biophys J. 2010 Jun 2;98(11):2564-73
20513400
Biophys J. 2004 Jul;87(1):675-87
15240501
IDrugs. 2009 Jun;12(6):376-80
19517318
Biochim Biophys Acta. 2009 Jan;1788(1):289-94
18822270
J Immunol Methods. 1988 Apr 6;108(1-2):153-8
3127470
Biochemistry. 2006 May 9;45(18):5793-9
16669623
Nat Rev Microbiol. 2009 Mar;7(3):245-50
19219054
Biochim Biophys Acta. 1998 Nov 10;1376(3):391-400
9804997
Biochemistry. 2008 Feb 26;47(8):2601-16
18220419
J Mol Biol. 2008 May 23;379(1):38-50
18440552
Curr Protein Pept Sci. 2006 Dec;7(6):479-86
17168781
Biochim Biophys Acta. 2010 Jun;1798(6):1272-80
20302840
Biochim Biophys Acta. 2008 Feb;1778(2):357-75
18078805
J Am Chem Soc. 2008 Oct 29;130(43):14346-52
18826221
Biochemistry. 2008 Jun 17;47(24):6394-402
18500827
Mol Biosyst. 2009 Jun;5(6):580-7
19462015
J Invest Dermatol. 2008 Jun;128(6):1525-34
18185531
FASEB J. 2008 Aug;22(8):2652-61
18385215
Biochimie. 2009 Jun;91(6):734-43
19455745
Biochim Biophys Acta. 2005 Jun 1;1711(1):49-58
15904663