Abstract
Several antimicrobial peptides (AMPs) have been discovered, developed, and purified from natural sources and peptide engineering; however, the clinical applications of these AMPs are limited owing to their lack of abundance and side effects related to cytotoxicity, immunogenicity, and hemolytic activity. Accordingly, to improve cell selectivity for pseudin-2, an AMP from Pseudis paradoxa skin, in mammalian cells and pathogenic fungi, the sequence of pseudin-2 was modified by alanine or lysine at each position of two amino acids within the leucine-zipper motif. Alanine-substituted variants were highly selective toward fungi over HaCaT and erythrocytes and maintained their antifungal activities and mode of action (membranolysis). However, the antifungal activities of lysine-substituted peptides were reduced, and the compound could penetrate into fungal cells, followed by induction of mitochondrial reactive oxygen species and cell death. In vivo antifungal assays of analogous peptide showed excellent antifungal efficiency in a Candida tropicalis skin infection mouse model. Our results demonstrated the usefulness of selective amino acid substitution in the repeated sequence of the leucine-zipper motif for the design of AMPs with potent antimicrobial activities and low toxicity.
Highlights
The increasing emergence of pathogens showing resistance to conventional drugs and the increasing frequency of microbial infections in immunosuppressed hosts have necessitated the identification of new types of antibiotics showing different mechanisms for the prevention of infection [1,2]
Amino acids forming a scissors shape are connected at seven sites, and the inner parts are interlocked at sites of leucine residues
We suggest that the difference of minimum inhibitory concentrations (MICs) values against each fungus is determined by the compositions of the cell wall of each fungus and P2-LZ4 has a high affinity with them
Summary
The increasing emergence of pathogens showing resistance to conventional drugs and the increasing frequency of microbial infections in immunosuppressed hosts have necessitated the identification of new types of antibiotics showing different mechanisms for the prevention of infection [1,2]. AMPs are involved in the innate host defense system as a primary barrier against infection in most organisms. Studies of AMPs have investigated their abundance in nature, their mechanisms, and their roles in innate or adaptive immune systems, as well as the effects of amino acid modification and their functions in drug delivery systems [8,9,10,11,12,13,14,15].
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