The interaction of the antimicrobial peptide gramicidin S with lipid bilayer model and biological membranes

• Published in: BBA - Biomembranes Vol. 1462; no. 1; pp. 201 - 221
• Main Authors: Prenner, Elmar J, Lewis, Ruthven N.A.H, McElhaney, Ronald N
• Format: Book Review Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.12.1999
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Infective Agents, Local - chemistry; Antimicrobial peptide; Bacteria - chemistry; Biological membrane; Calorimetry, Differential Scanning; Cell Membrane - chemistry; Differential scanning calorimetry; Electron spin resonance spectroscopy; Fluorescence spectroscopy; Fourier transform infrared spectroscopy; Gramicidin - chemistry; Gramicidin S; Intracellular Membranes - chemistry; Lipid bilayer; Lipid Bilayers - chemistry; Magnetic Resonance Spectroscopy; Membrane lysis; Membrane permeability; Model membrane; Models, Molecular; Nuclear magnetic resonance spectroscopy; Permeability; Phospholipids - chemistry; Protein Conformation; Spectrometry, Fluorescence; Spectroscopy, Fourier Transform Infrared; Structure-Activity Relationship; Thermodynamics; Fluorescence spectroscopy; Membrane permeability; P- O-E-DMPC, phosphoethyl derivative of DMPC; Electron spin resonance spectroscopy; SUV, small unilamellar vesicle; T m, gel to liquid–crystalline phase transition temperature; DGDG, diglucosyl diacylglycerol; Gramicidin S; Membrane lysis; NMR, nuclear magnetic resonance; Lipid bilayer; LS- and HS-DSC, low- and high-sensitivity differential scanning calorimetry; DPEPE, dipalmitelaidoylphosphatidylethanolamine; DPH, diphenylhexatriene; PA, phosphatidic acid; PC, phosphatidylcholine; FTIR, Fourier transform infrared; MLV, large multilamellar vesicle; Differential scanning calorimetry; MIC, minimum inhibitory concentration; GS, gramicidin S; Nuclear magnetic resonance spectroscopy; MGDG, monoglucosyl diacylglycerol; PE, phosphatidylethanolamine; PS, phosphatidylserine; ESR, electron spin resonance; PG, phosphatidylglycerol; DEPC, dielaidoylphosphatidylcholine; Δ H, gel to liquid–crystalline phase transition enthalpy; Model membrane; POPC, 1-palmitoyl-2-oleoyl phosphatidylcholine; Biological membrane; DPPC, dipalmitoylphosphatidylcholine (or other phospholipid); Fourier transform infrared spectroscopy; DMPC, dimyristoylphosphatidylcholine; Antimicrobial peptide
• ISSN: 0005-2736; 0006-3002; 1879-2642
• DOI: 10.1016/S0005-2736(99)00207-2

Gramicidin S (GS) is a cyclic decapeptide of primary structure [cyclo-(Val-Orn-Leu- d-Phe-Pro) 2] secreted by Bacillus brevis. It is a powerful antimicrobial agent with potent cidal action on a wide variety of Gram-negative and Gram-positive bacteria as well as on several pathogenic fungi. Unfortunately, however, GS is rather non-specific in its actions and also exhibits a high hemolytic activity, limiting its use as an antibiotic to topical applications. In a wide variety of environments, the GS molecule exists as a very stable amphiphilic antiparallel β-sheet structure with a polar and a non-polar surface. Moreover, the large number of structure–activity studies of GS analogs which have been carried out indicate that this ‘sidedness’ structure is required for its antimicrobial action. In this review, we summarize both published and unpublished biophysical studies of the interactions of GS with lipid bilayer model and with biological membranes. In general, these studies show that GS partitions strongly into liquid–crystalline lipid bilayers in both model and biological membranes, and seems to be located primarily in the glycerol backbone region below the polar headgroups and above the hydrocarbon chains. The presence of GS appears to perturb lipid packing in liquid–crystalline bilayers and GS can induce the formation of inverted cubic phases at lower temperatures in lipids capable of forming such phases at higher temperature in the absence of peptide. The presence of GS at lower concentrations also increases the permeability of model and biological membranes and at higher concentrations causes membrane destabilization. There is good evidence from studies of the interaction of GS with bacterial cells that the destruction of the integrity of the lipid bilayer of the inner membrane is the primary mode of the antimicrobial action of this peptide. The considerable lipid specificity of GS for binding to and destabilization of lipid bilayer model membranes indicates that the design of GS analogs with an improved antimicrobial potency and a markedly decreased toxicity for eukaryotic cell plasma membranes should be possible.