The Human Antimicrobial Peptides Dermcidin and LL-37 Show Novel Distinct Pathways in Membrane Interactions

Abstract

Mammals protect themselves from inflammation triggered by microorganisms through secretion of antimicrobial peptides (AMPs). One mechanism by which AMPs kill bacterial cells is perforating their membranes. Membrane interactions and pore formation were investigated for α-helical AMPs leading to the formulation of three basic mechanistic models: the barrel stave, toroidal, and carpet model. One major drawback of these models is their simplicity. They do not reflect the real in vitro and in vivo conditions. To challenge and refine these models using a structure-based approach we set out to investigate how human cathelicidin (LL-37) and dermcidin (DCD) interact with membranes. Both peptides are α-helical and their structures have been solved at atomic resolution. DCD assembles in solution into a hexameric pre-channel complex before the actual membrane targeting and integration step can occur, and the complex follows a deviation of the barrel stave model. LL-37 interacts with lipids and shows the formation of oligomers generating fibril-like supramolecular structures on membranes. LL-37 further assembles into transmembrane pores with yet unknown structure expressing a deviation of the toroidal pore model. Both of their specific targeting mechanisms will be discussed in the context of the “old” models propagated in the literature.

A new clinical tool to predict outcome in early-stage melanoma patients

“…Our previous attempt to identify novel serological prognostic markers identified a threshold for serological DCD that was associated with a poor prognosis value for melanoma patients diagnosed specifically at AJCC stage II 23 . Consistent with this finding, DCD, a major human antimicrobial peptide in human skin 24,25 was also recently proposed as a serological marker for the diagnosis and staging of hepatocellular carcinoma 31 .…”

“…In a previous study carried out on a large group of melanoma patients, and based on serum proteomic analysis and immunoassays, we established prognostic value of serum Dermcidin (DCD) for stage II melanoma patients 23 . DCD is considered to play an important role in the cutaneous microenvironment due to its antimicrobial activity 24 . Nevertheless, DCD is not just an antimicrobial peptide as it can stimulate keratinocytes to produce cytokines though G-protein and mitogen-activated protein kinase activation 25 .…”

Antimicrobial peptides under clinical investigation

“…In this case, the covalent linkage is used to generate AMP oligomers as exemplified by dimeric B2108 or tetrameric B4010 . These multimeric peptides exhibit much higher antimicrobial activity compared with the monomeric peptide …”

Mechanisms of Action for Antimicrobial Peptides With Antibacterial and Antibiofilm Functions

“…The pore forming mechanisms, which have been characterized extensively in many papers (e.g., reviewed in Kumar et al, 2018), are shown in more detail. (Cheng et al, 2011;Wenzel et al, 2015); Magainin (Matsuzaki et al, 1998); HNP-1 (de Leeuw et al, 2010); Cg-Defh1 (Schmitt et al, 2010); Thanatin (Sinha et al, 2017); Esculentin-1a (Luca et al, 2013); LL-37 (Zeth and Sancho-Vaello, 2017) DNA target MIC; MBC -bactericidal a /Gel electrophoresis Buforin II (Park et al, 1998;Kobayashi et al, 2000Kobayashi et al, , 2004Xie et al, 2011); Indolicidin (Hsu et al, 2005;Marchand et al, 2006;Hale and Hancock, 2007;Hilpert et al, 2010) RNA target MIC; MBC -generally bacteriostatic a /Gel electrophoresis Attacin (Carlsson et al, 1991) Protein target MIC; MBC -generally bacteriostatic a /Co-precipitation; fluorescence Other target MBIC; MBEC e.g., gene down-regulation/targeting Nal-P-113 ; human β-defensin 3 (Zhu et al, 2013) a Based on (Finberg et al, 2004).…”