Abstract
Ultrashort cationic lipopeptides (USCLs) are considered to be a promising class of antimicrobials with high activity against a broad-spectrum of microorganisms. However, the majority of these compounds are characterized by significant toxicity toward human cells, which hinders their potential application. To overcome those limitations, several approaches have been advanced. One of these is disulfide cyclization that has been shown to improve drug-like characteristics of peptides. In this article the effect of disulfide cyclization of the polar head of N-palmitoylated USCLs on in vitro biological activity has been studied. Lipopeptides used in this study consisted of three or four basic amino acids (lysine and arginine) and cystine in a cyclic peptide. In general, disulfide cyclization of the lipopeptides resulted in peptides with reduced cytotoxicity. Disulfide-cyclized USCLs exhibited improved selectivity between Candida sp., Gram-positive strains and normal cells in contrast to their linear counterparts. Interactions between selected USCLs and membranes were studied by molecular dynamics simulations using a coarse-grained force field. Moreover, membrane permeabilization properties and kinetics were examined. Fluorescence and transmission electron microscopy revealed damage to Candida cell membrane and organelles. Concluding, USCLs are strong membrane disruptors and disulfide cyclization of polar head can have a beneficial effect on its in vitro selectivity between Candida sp. and normal human cells.
Highlights
The development of new antimicrobial agents seems to be fundamental, especially when considering dramatically increasing antimicrobial resistance [1]
The most selective compound was a cyclic lipopeptide with one arginine and three lysine residues, (C4) C16-CKRKKC-NH2
It has been shown that Ultrashort cationic lipopeptides (USCLs) can be promising anti-biofilm and antimicrobial coatings and components of formulations with biodegradable polymers [50,83]
Summary
The development of new antimicrobial agents seems to be fundamental, especially when considering dramatically increasing antimicrobial resistance [1]. Ultrashort (up to 7 amino acid residues) cationic lipopeptides (USCLs) have been claimed to be effective antimicrobial agents [5,6,7,8]. These molecules have a detergent-like mode of action and their membrane—cation interactions partially rely on the electrostatic attraction between positively charged amino acid residues and negatively charged membrane components. Lipopeptides can exhibit, inter alia, anticancer, antibacterial, antifungal, antibiofilm, and antiadhesive activities but their application can be limited due to hemolytic potential and cytotoxicity against normal cells These properties make them perfect candidates for further studies and optimization of the structure. Compounds with free sulfhydryl groups (Figure 1B) have not been studied due to their high susceptibility to oxidation [22]
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