Membrane Core-Specific Antimicrobial Action of Cathelicidin LL-37 Peptide Switches Between Pore and Nanofibre Formation

Abstract

Membrane-disrupting antimicrobial peptides provide broad-spectrum defence against localized bacterial invasion in a range of hosts including humans. The most generally held consensus is that targeting to pathogens is based on interactions with the head groups of membrane lipids. Here we show that the action of LL-37, a human antimicrobial peptide switches the mode of action based on the structure of the alkyl chains, and not the head groups of the membrane forming lipids. We demonstrate that LL-37 exhibits two distinct interaction pathways: pore formation in bilayers of unsaturated phospholipids and membrane modulation with saturated phospholipids. Uniquely, the membrane modulation yields helical-rich fibrous peptide-lipid superstructures. Our results point at alternative design strategies for peptide antimicrobials.

Structural remodeling and oligomerization of human cathelicidin on membranes suggest fibril-like structures as active species

“…6 ). Also in line with our observation of fiber-like structures are reports demonstrating the formation of one-dimensional peptide chains by the designer peptide LAH4, BTD-2 and LL-37 on vesicles pointing towards a similar mode of self-organization patterning 24 – 27 . However, these observations are only indirect, using imaging techniques, while our structures are at the atomic level and show the fiber assembly.…”

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

“…In the first step, LL-37 interacts with LPS and LTA and possibly removes part of these molecules from the cell wall (Neville et al, 2006 ). In the second step, according to our own data and the data of others implies that LL-37 can specifically interact with membranes or even specifically with individual lipid head groups via a multi-step mechanism (Scientific reports in press; Shahmiri et al, 2016 ; Figure 2D ). This mechanism is more complicated than the simple toroidal model, where the monomeric peptide assembles on the membrane to form holes on lipid-peptide complexes (Ludtke et al, 1996 ; Matsuzaki et al, 1996 ).…”

“…These fiber-like structures could also be detected on vesicles using gold-labeled LL-37 and electron microscopy as imaging technique (Scientific reports in press). LL-37 has previously been shown to restructure lipid vesicles into elongated structures, possibly based on the formation of a similar supramolecular structure (Shahmiri et al, 2016 ). The formation of such fiber-like structures has been described previously for the synthetic peptides LAH4 and BTD-2 (Aisenbrey and Bechinger, 2014 ; Wang et al, 2016 ; Figure 2E ).…”

“…(E) Related models and experimental data which were recently published in the literature are based on fluorescence techniques applied to LAH4, crystallography and analysis of crystal packing of BTD-2 and electron microscopy of LL-37 mixed with lipid vesicles (Aisenbrey and Bechinger, 2014 ; Shahmiri et al, 2016 ; Wang et al, 2016 ). LL-37 TEM figure is reprinted from Shahmiri et al ( 2016 ) published in open-access under CC BY 4.0 license. LAH4 figure is reprinted with permission from by Aisenbrey and Bechinger ( 2014 ).…”

The Human Cathelicidin Antimicrobial Peptide LL-37 Promotes the Growth of the Pulmonary Pathogen Aspergillus fumigatus

“…For example, Helicobacter pylori displays resistance to LL-37 that is dependent on scavenging and utilization of host cholesterol (20). Interestingly, LL-37 can induce some degree of leakage in unsaturated and cholesterol-containing membranes (21). LL-37 displays candidacidal activity by targeting the fungal membrane, resulting in complete membrane disintegration and efflux of cellular ATP and protein (22).…”