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Fatty Acid Conjugation Leads to Length-Dependent Antimicrobial Activity of a Synthetic Antibacterial Peptide (Pep19-4LF)

The increasing number of infections caused by multidrug-resistant bacteria requires an intensified search for new antibiotics. Pep19-4LF is a synthetic antimicrobial peptide (GKKYRRFRWKFKGKLFLFG) that was previously designed with the main focus on high antimicrobial activity. The hydrophobic motif,...

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Autores principales: Storck, Philip, Umstätter, Florian, Wohlfart, Sabrina, Domhan, Cornelius, Kleist, Christian, Werner, Julia, Brandenburg, Klaus, Zimmermann, Stefan, Haberkorn, Uwe, Mier, Walter, Uhl, Philipp
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760514/
https://www.ncbi.nlm.nih.gov/pubmed/33255900
http://dx.doi.org/10.3390/antibiotics9120844
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author Storck, Philip
Umstätter, Florian
Wohlfart, Sabrina
Domhan, Cornelius
Kleist, Christian
Werner, Julia
Brandenburg, Klaus
Zimmermann, Stefan
Haberkorn, Uwe
Mier, Walter
Uhl, Philipp
author_facet Storck, Philip
Umstätter, Florian
Wohlfart, Sabrina
Domhan, Cornelius
Kleist, Christian
Werner, Julia
Brandenburg, Klaus
Zimmermann, Stefan
Haberkorn, Uwe
Mier, Walter
Uhl, Philipp
author_sort Storck, Philip
collection PubMed
description The increasing number of infections caused by multidrug-resistant bacteria requires an intensified search for new antibiotics. Pep19-4LF is a synthetic antimicrobial peptide (GKKYRRFRWKFKGKLFLFG) that was previously designed with the main focus on high antimicrobial activity. The hydrophobic motif, LFLFG, was found to be essential for antimicrobial activity. However, this motif shows several limitations such as aggregation in biological media, low solubility, and small yields in peptide synthesis. In order to obtain more appropriate peptide characteristics, the hydrophobic motif was replaced with fatty acids. For this purpose, a shortened variant of Pep19-4LF (Pep19-short; GKKYRRFRWKFKGK) was synthesized and covalently linked to saturated fatty acids of different chain lengths. The peptide conjugates were tested with respect to their antibacterial activity by microdilution experiments on different bacterial strains. The length of the fatty acid was found to be directly correlated to the antimicrobial activity up to an ideal chain length (undecanoic acid, C11:0). This conjugate showed high antimicrobial activity in absence of toxicity. Time–kill studies revealed a fast and bactericidal mode of action. Furthermore, the first in vivo experiments of the conjugate in rodents demonstrated pharmacokinetics appropriate for application as a drug. These results clearly indicate that the hydrophobic motif of the peptide can be replaced by a single fatty acid of medium length, simplifying the design of this antimicrobial peptide while retaining high antimicrobial activity in the absence of toxicity.
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spelling pubmed-77605142020-12-26 Fatty Acid Conjugation Leads to Length-Dependent Antimicrobial Activity of a Synthetic Antibacterial Peptide (Pep19-4LF) Storck, Philip Umstätter, Florian Wohlfart, Sabrina Domhan, Cornelius Kleist, Christian Werner, Julia Brandenburg, Klaus Zimmermann, Stefan Haberkorn, Uwe Mier, Walter Uhl, Philipp Antibiotics (Basel) Article The increasing number of infections caused by multidrug-resistant bacteria requires an intensified search for new antibiotics. Pep19-4LF is a synthetic antimicrobial peptide (GKKYRRFRWKFKGKLFLFG) that was previously designed with the main focus on high antimicrobial activity. The hydrophobic motif, LFLFG, was found to be essential for antimicrobial activity. However, this motif shows several limitations such as aggregation in biological media, low solubility, and small yields in peptide synthesis. In order to obtain more appropriate peptide characteristics, the hydrophobic motif was replaced with fatty acids. For this purpose, a shortened variant of Pep19-4LF (Pep19-short; GKKYRRFRWKFKGK) was synthesized and covalently linked to saturated fatty acids of different chain lengths. The peptide conjugates were tested with respect to their antibacterial activity by microdilution experiments on different bacterial strains. The length of the fatty acid was found to be directly correlated to the antimicrobial activity up to an ideal chain length (undecanoic acid, C11:0). This conjugate showed high antimicrobial activity in absence of toxicity. Time–kill studies revealed a fast and bactericidal mode of action. Furthermore, the first in vivo experiments of the conjugate in rodents demonstrated pharmacokinetics appropriate for application as a drug. These results clearly indicate that the hydrophobic motif of the peptide can be replaced by a single fatty acid of medium length, simplifying the design of this antimicrobial peptide while retaining high antimicrobial activity in the absence of toxicity. MDPI 2020-11-26 /pmc/articles/PMC7760514/ /pubmed/33255900 http://dx.doi.org/10.3390/antibiotics9120844 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
Storck, Philip
Umstätter, Florian
Wohlfart, Sabrina
Domhan, Cornelius
Kleist, Christian
Werner, Julia
Brandenburg, Klaus
Zimmermann, Stefan
Haberkorn, Uwe
Mier, Walter
Uhl, Philipp
Fatty Acid Conjugation Leads to Length-Dependent Antimicrobial Activity of a Synthetic Antibacterial Peptide (Pep19-4LF)
title Fatty Acid Conjugation Leads to Length-Dependent Antimicrobial Activity of a Synthetic Antibacterial Peptide (Pep19-4LF)
title_full Fatty Acid Conjugation Leads to Length-Dependent Antimicrobial Activity of a Synthetic Antibacterial Peptide (Pep19-4LF)
title_fullStr Fatty Acid Conjugation Leads to Length-Dependent Antimicrobial Activity of a Synthetic Antibacterial Peptide (Pep19-4LF)
title_full_unstemmed Fatty Acid Conjugation Leads to Length-Dependent Antimicrobial Activity of a Synthetic Antibacterial Peptide (Pep19-4LF)
title_short Fatty Acid Conjugation Leads to Length-Dependent Antimicrobial Activity of a Synthetic Antibacterial Peptide (Pep19-4LF)
title_sort fatty acid conjugation leads to length-dependent antimicrobial activity of a synthetic antibacterial peptide (pep19-4lf)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760514/
https://www.ncbi.nlm.nih.gov/pubmed/33255900
http://dx.doi.org/10.3390/antibiotics9120844
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