Dermcidin (DCD) is constitutively expressed in eccrine sweat glands, secreted into sweat and transported to the epidermal surface where it is proteolytically processed giving rise to several truncated DCD peptides (Schittek B et al. 2001; Rieg S et al. 2006). The processed forms such as the anionic DCD(63-110) (DCD-1L) and DCD(63-109) (DCD-1) possess antimicrobial activity against Gram-positive (Staphylococcus aureus, Enterococcus faecalis, Staphylococcus epidermidis, Listeria monocytogenes) and Gram-negative bacteria (Escherichia coli, Pseudomonas putida, Salmonella typhimurium) as well as Candida albicans (Cipakova I et al. 2006; Lai YP et al. 2005; Schittek B et al. 2001; Steffen H et al. 2006; Vuong C et al. 2004). The antimicrobial activity of DCD(63-110) (DCD-1L) is maintained over a broad pH range and at high salt concentrations that resemble the conditions in human sweat (Schittek B et al. 2001). DCD(63-110) was reported to interact with negatively charged bacterial phospholipids which lead to (Zn2+)-dependent formation of oligomeric complexes in the bacterial membrane, which subsequently lead to ion channel formation resulting in membrane depolarization and bacterial cell death (Paulmann M et al. 2012; Song C et al. 2013).

DCD peptide is initially monomeric when secreted in human sweat. In presence of a negatively charged bacterial membrane the cationic N-terminus of DCD gets attracted electrostatically (Paulmann M et al. 2012). Upon interaction with the bacterial membrane a change in the secondary structure from random coil to an alpha-helical conformation is induced. DCD-1(L) self-assembles into a higher oligomeric state which is stabilized by zinc ions. Subsequently, by oligomerization DCD is able to form ion channels in the bacterial membrane resulting in bacterial cell death ( (Paulmann M et al. 2012; Song C et al. 2013; Burian M & Schittek B 2015).

Dermcidin peptides, DCD1(63-109) and DCD-1L(63-110), are anionic peptides with a net negative charge of -2 at physiological pH (Paulmann M et al. 2012). Despite its negative net charge, DCD peptides possess an amphiphilic structure due to its cationic N-terminal region (Ser1 to Lys23) and its anionic C-terminal part (Asp24 to Leu48). The cationic N-terminal part is mainly responsible for the binding of DCD to the negatively charged phospholipids.

A 47aa dermcidin (DCD)-derived peptide (DCD(63-109), also known as as DCD-1) is an antimicrobial peptide with a negative net charge and acidic pI (Schittek B 2012). Like other antimicrobially active DCD-derived peptides, DCD(63-109) is produced in human eccrine sweat through proteolytic processing of a 110-amino acid (aa) precursor protein (Schittek B et al. 2001; Rieg S et al. 2006). DCD-derived peptides are able to bind to the bacterial surface, however they do not exert their activity by permeabilizing bacterial membranes (Senyürek et al. 2009, Steffen H et al. 2006). The negative net charge of DCD(63-109) did not significantly affected the peptide binding to bacterial-mimetic membranes (Jung et al. 2010, Steffen et al. 2006; Senyurek et al. 2009). Spin-down assays of DCD(63-109) and other DCD peptides revealed that the affinity with which dermcidin binds to bacterial-mimetic membranes is primarily dependent on its amphipathic alpha-helical structure and its length (>30 residues)(Jung et al. 2010).

DCD(63-109) shows a broad spectrum of antimicrobial activity against Gram-positive (Staphylococcus aureus, Enterococcus faecalis, Staphylococcus epidermidis, Listeria monocytogenes) and Gram-negative bacteria (Escherichia coli, Pseudomonas putida, Salmonella typhimurium) as well as Candida albicans (Cipakova I et al. 2006, Lai YP et al. 2005, Schittek B et al. 2001, Steffen H et al. 2006, Vuong C et al. 2004). The activity of the DCD(63-109) was maintained over a broad pH range and in high salt concentrations that resembled the conditions in human sweat (Schittek B et al. 2001).

Antimicrobial peptides (AMPs) are small molecular weight proteins with broad spectrum of antimicrobial activity against bacteria, viruses, and fungi (Zasloff M 2002; Radek K & Gallo R 2007). The majority of known AMPs are cationic peptides with common structural characteristics where domains of hydrophobic and cationic amino acids are spatially arranged into an amphipathic design, which facilitates their interaction with bacterial membranes (Shai Y 2002; Yeaman MR & Yount NY 2003; Brown KL & Hancock RE 2006; Dennison SR et al. 2005; Zelezetsky I & Tossi A 2006). It is generally excepted that the electrostatic interaction facilitates the initial binding of the positively charged peptides to the negatively charged bacterial membrane. Moreover, the structural amphiphilicity of AMPs is thought to promote their integration into lipid bilayers of pathogenic cells, leading to membrane disintegration and finally to the microbial cell death. In addition to cationic AMPs a few anionic antimicrobial peptides have been found in humans, however their mechanism of action remains to be clarified (Lai Y et al. 2007; Harris F et al. 2009; Paulmann M et al. 2012). Besides the direct neutralizing effects on bacteria AMPs may modulate cells of the adaptive immunity (neutrophils, T-cells, macrophages) to control inflammation and/or to increase bacterial clearance.

AMPs have also been referred to as cationic host defense peptides, anionic antimicrobial peptides/proteins, cationic amphipathic peptides, cationic AMPs, host defense peptides and alpha-helical antimicrobial peptides (Brown KL & Hancock RE 2006; Harris F et al. 2009; Groenink J et al. 1999; Bradshaw J 2003; Riedl S et al. 2011; Huang Y et al. 2010).

The Reactome module describes the interaction events of various types of human AMPs, such as cathelicidin, histatins and neutrophil serine proteases, with conserved patterns of microbial membranes at the host-pathogen interface. The module includes also proteolytic processing events for dermcidin (DCD) and cathelicidin (CAMP) that become functional upon cleavage. In addition, the module highlights an AMP-associated ability of the host to control metal quota at inflammation sites to influence host-pathogen interactions.