Dermcidin is a human antibiotic peptide that is secreted by the sweat glands and has no homology to other known antimicrobial peptides. As an initial step toward understanding dermcidin's mode of action at bacterial membranes, we used homonuclear and heteronuclear NMR to determine the conformation of the peptide in 50% trifluoroethanol solution. We found that dermcidin adopts a flexible amphipathic α-helical structure with a helix-hinge-helix motif, which is a common molecular fold among antimicrobial peptides. Spin-down assays of dermcidin and several related peptides revealed that the affinity with which dermcidin binds to bacterial-mimetic membranes is primarily dependent on its amphipathic α-helical structure and its length (＞30 residues); its negative net charge and acidic pI have little effect on binding. These findings suggest that the mode of action of dermcidin is similar to that of other membrane-targeting antimicrobial peptides, though the details of its antimicrobial action remain to be determined [BMB reports 2010; 43(5): 362-368]

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Dermcidin is a human antibiotic peptide that is secreted by the sweat glands and has no homology to other known antimicrobial peptides. As an initial step toward understanding dermcidin's mode of action at bacterial membranes, we used homonuclear and heteronuclear NMR to determine the conformation of the peptide in 50% trifluoroethanol solution. We found that dermcidin adopts a flexible amphipathic α-helical structure with a helix-hinge-helix motif, which is a common molecular fold among antimicrobial peptides. Spin-down assays of dermcidin and several related peptides revealed that the affinity with which dermcidin binds to bacterial-mimetic membranes is primarily dependent on its amphipathic α-helical structure and its length (＞30 residues); its negative net charge and acidic pI have little effect on binding. These findings suggest that the mode of action of dermcidin is similar to that of other membrane-targeting antimicrobial peptides, though the details of its antimicrobial action remain to be determined [BMB reports 2010; 43(5): 362-368] INTRODUCTIONAntimicrobial peptides are produced in a wide range of animals for innate host defense and show a broad spectrum of antimicrobial activity (1-4). Despite the remarkable diversity of their amino acid compositions, antimicrobial peptides show several common features, including the presence of multiple basic amino acids and amphipathic structures with clusters of hydrophobic and hydrophilic amino acids (5-8). Recent studies of the modes of action of various antimicrobial peptides have revealed that their cationic nature contributes to their initial binding to negatively charged bacterial membranes through electrostatic interaction, while their amphipathic structures enhance peptide-lipid interactions at the water-bilayer interface, ultimately leading to cell death via pore formation or membrane disintergration (9-14).Dermcidin (DCD) is an antimicrobial peptide found in human sweat. It is produced through proteolytic processing of a 110-amino acid precursor protein that has no homology to other known antimicrobial peptides (15, 16). The processed peptide, DCD-1, has 47 amino acids and shows a broad spectrum of antimicrobial activity against a variety of pathogenic microorganisms (15,17,18). Using immune-EM, it was recently shown that the antimicrobial activity of DCD-1 originates with its binding to the bacterial membrane, and that it effectively kills Staphylococcus epidermidis (18).DCD-1L, which is produced by adding a leucine residue to the C-terminus of DCD-1, shows stronger antimicrobial activity than the parent peptide (15). It is especially noteworthy that DCD-1L exhibits activity against drug-resistant S. aureus, as well as other Gram-positive and Gram-negative bacterial strains (17). In the present study, we used nuclear magnetic resonance (NMR) spectroscopy to determine, for the first time, the solution structure of DCD-1L in a bacterial membrane-mimetic environment. In addition, to investigate the interaction between DCD-1L and bacterial membranes, we sy...

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Antimicrobial peptides (AMPs) are cationic antibiotics that can kill multidrug-resistant bacteria via membrane insertion. However, their weak activity limits their clinical use. Ironically, the cationic charge of AMPs is essential for membrane binding, but it obstructs membrane insertion. In this study, we postulate that this problem can be overcome by locating cationic amino acids at the energetically preferred membrane surface. All amino acids have an energetically preferred or less preferred membrane position profile, and this profile is strongly related to membrane insertion. However, most AMPs do not follow this profile. One exception is protegrin-1, a powerful but neglected AMP. In the present study, we found that a potent AMP, WCopW5, strongly resembles protegrin-1 and that the match between its sequence and the preferred position profile closely correlates with its antimicrobial activity. One of its derivatives, WCopW43, has antimicrobial activity comparable to that of the most effective AMPs in clinical use.