Vicin-like antimicrobial peptide 2d

Antimicrobial peptides are promising molecules to address the global antibiotic resistance problem, however, optimization to achieve favorable potency and safety is required. Here, a peptide-template modification approach was employed to design physicochemical variants based on net charge, hydrophobicity, enantiomer, and terminal group. All variants of the scorpion venom peptide BmKn-2 with amphipathic α-helical cationic structure exhibited an increased antibacterial potency when evaluated against multidrug-resistant Salmonella isolates at a MIC range of 4-8 µM. They revealed antibiofilm activity in a dose-dependent manner. Sheep red blood cells were used to evaluate hemolytic and cell selectivity properties. Peptide Kn2-5R-NH2, dKn2-5R-NH2, and 2F-Kn2-5R-NH2 (variants with +6 charges carrying amidated C-terminus) showed stronger antibacterial activity than Kn2-5R (a variant with +5 charges bearing free-carboxyl group at C-terminus). Peptide dKn2-5R-NH2 (d-enantiomer) exhibited slightly weaker antibacterial activity with much less hemolytic activity (higher hemolytic concentration 50) than Kn2-5R-NH2 (l-enantiomer). Furthermore, peptide Kn2-5R with the least hydrophobicity had the lowest hemolytic activity and showed the highest specificity to Salmonella (the highest selectivity index). This study also explained the relationship of peptide physicochemical properties and bioactivities that would fulfill and accelerate progress in peptide antibiotic research and development.

Generalized pustular psoriasis (GPP) is a chronic disease characterized by non-bacterial pustules. Variants in several genes, such as IL36RN, AP1S3, and CARD14, are involved in the pathogenesis of GPP. The prevalence of different gene variants varies among ethnicities, and some variants are related to concurrent psoriasis vulgaris or age at onset. Flares can be triggered by medications (most commonly corticosteroids), infections (possibly due to Toll-like receptor [TLR] and antimicrobial peptides), pregnancy (the onset of GPP has been attributed to endocrine abnormalities such as hypoparathyroidism and hypocalcaemia), hypocalcaemia (presumably due to low levels of calcium and vitamin D regulating the proliferation and differentiation of keratinocytes), and other factors including stress and sun exposure. The mechanisms of pustule formation involve: 1) the LL37/TLR pathway, in which LL37 acts as an alarmin, interacting with TLR and activating the NF-κB and MAPK pathways; 2) the balance between calcium and 1,25(OH)2D levels, and 3) neutrophils and the complement system.

Vitamin D plays a pivotal role in intestinal homeostasis. Vitamin D can impact the function of virtually every cell in the gut by binding to its intracellular receptor (VDR) and subsequently transcribing relevant genes. In the lumen, the mucus layer and the underlying epithelium serve to keep resident microbiota at bay. Vitamin D ensures an appropriate level of antimicrobial peptides in the mucus and maintains epithelial integrity by reinforcing intercellular junctions. Should bacteria penetrate the epithelial layer and enter the interstitium, immune sentinel cells (e.g. macrophages, dendritic cells, and innate lymphoid cells) elicit inflammation and trigger the adaptive immune response by activating Th1/Th17 cells. Vitamin D/VDR signaling in these cells ensures clearance of the bacteria. Subsequently, vitamin D also quiets the adaptive immune system by suppressing the Th1/Th17 cells and favoring Treg cells. The importance of vitamin D/VDR signaling in intestinal homeostasis is evidenced by the development of a chronic inflammatory state (e.g. IBD) when this signaling system is disrupted.