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Effect of Disulfide Cyclization of Ultrashort Cationic Lipopeptides on Antimicrobial Activity and Cytotoxicity

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 applic...

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Autores principales: Neubauer, Damian, Jaśkiewicz, Maciej, Sikorska, Emilia, Bartoszewska, Sylwia, Bauer, Marta, Kapusta, Małgorzata, Narajczyk, Magdalena, Kamysz, Wojciech
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582905/
https://www.ncbi.nlm.nih.gov/pubmed/33003569
http://dx.doi.org/10.3390/ijms21197208
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author Neubauer, Damian
Jaśkiewicz, Maciej
Sikorska, Emilia
Bartoszewska, Sylwia
Bauer, Marta
Kapusta, Małgorzata
Narajczyk, Magdalena
Kamysz, Wojciech
author_facet Neubauer, Damian
Jaśkiewicz, Maciej
Sikorska, Emilia
Bartoszewska, Sylwia
Bauer, Marta
Kapusta, Małgorzata
Narajczyk, Magdalena
Kamysz, Wojciech
author_sort Neubauer, Damian
collection PubMed
description 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.
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spelling pubmed-75829052020-10-28 Effect of Disulfide Cyclization of Ultrashort Cationic Lipopeptides on Antimicrobial Activity and Cytotoxicity Neubauer, Damian Jaśkiewicz, Maciej Sikorska, Emilia Bartoszewska, Sylwia Bauer, Marta Kapusta, Małgorzata Narajczyk, Magdalena Kamysz, Wojciech Int J Mol Sci Article 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. MDPI 2020-09-29 /pmc/articles/PMC7582905/ /pubmed/33003569 http://dx.doi.org/10.3390/ijms21197208 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Neubauer, Damian
Jaśkiewicz, Maciej
Sikorska, Emilia
Bartoszewska, Sylwia
Bauer, Marta
Kapusta, Małgorzata
Narajczyk, Magdalena
Kamysz, Wojciech
Effect of Disulfide Cyclization of Ultrashort Cationic Lipopeptides on Antimicrobial Activity and Cytotoxicity
title Effect of Disulfide Cyclization of Ultrashort Cationic Lipopeptides on Antimicrobial Activity and Cytotoxicity
title_full Effect of Disulfide Cyclization of Ultrashort Cationic Lipopeptides on Antimicrobial Activity and Cytotoxicity
title_fullStr Effect of Disulfide Cyclization of Ultrashort Cationic Lipopeptides on Antimicrobial Activity and Cytotoxicity
title_full_unstemmed Effect of Disulfide Cyclization of Ultrashort Cationic Lipopeptides on Antimicrobial Activity and Cytotoxicity
title_short Effect of Disulfide Cyclization of Ultrashort Cationic Lipopeptides on Antimicrobial Activity and Cytotoxicity
title_sort effect of disulfide cyclization of ultrashort cationic lipopeptides on antimicrobial activity and cytotoxicity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582905/
https://www.ncbi.nlm.nih.gov/pubmed/33003569
http://dx.doi.org/10.3390/ijms21197208
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