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Peptide/β-Peptoid Hybrids with Activity against Vancomycin-Resistant Enterococci: Influence of Hydrophobicity and Structural Features on Antibacterial and Hemolytic Properties

Infections with enterococci are challenging to treat due to intrinsic resistance to several antibiotics. Especially vancomycin-resistant Enterococcus faecium and Enterococcus faecalis are of considerable concern with a limited number of efficacious therapeutics available. From an initial screening o...

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Autores principales: Vestergaard, Martin, Skive, Bolette, Domraceva, Ilona, Ingmer, Hanne, Franzyk, Henrik
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197855/
https://www.ncbi.nlm.nih.gov/pubmed/34070683
http://dx.doi.org/10.3390/ijms22115617
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author Vestergaard, Martin
Skive, Bolette
Domraceva, Ilona
Ingmer, Hanne
Franzyk, Henrik
author_facet Vestergaard, Martin
Skive, Bolette
Domraceva, Ilona
Ingmer, Hanne
Franzyk, Henrik
author_sort Vestergaard, Martin
collection PubMed
description Infections with enterococci are challenging to treat due to intrinsic resistance to several antibiotics. Especially vancomycin-resistant Enterococcus faecium and Enterococcus faecalis are of considerable concern with a limited number of efficacious therapeutics available. From an initial screening of 20 peptidomimetics, 11 stable peptide/β-peptoid hybrids were found to have antibacterial activity against eight E. faecium and E. faecalis isolates. Microbiological characterization comprised determination of minimal inhibitory concentrations (MICs), probing of synergy with antibiotics in a checkerboard assay, time–kill studies, as well as assessment of membrane integrity. E. faecium isolates proved more susceptible than E. faecalis isolates, and no differences in susceptibility between the vancomycin-resistant (VRE) and -susceptible E. faecium isolates were observed. A test of three peptidomimetics (Ac-[hArg-βNsce](6)-NH(2), Ac-[hArg-βNsce-Lys-βNspe](3)-NH(2) and Oct-[Lys-βNspe](6)-NH(2)) in combination with conventional antibiotics (vancomycin, gentamicin, ciprofloxacin, linezolid, rifampicin or azithromycin) revealed no synergy. The same three potent analogues were found to have a bactericidal effect with a membrane-disruptive mode of action. Peptidomimetics Ac-[hArg-βNsce-Lys-βNspe](3)-NH(2) and Oct-[Lys-βNspe](6)-NH(2) with low MIC values (in the ranges 2–8 µg/mL and 4–16 µg/mL against E. faecium and E. faecalis, respectively) and displaying weak cytotoxic properties (i.e., <10% hemolysis at a ~100-fold higher concentration than their MICs; IC(50) values of 73 and 41 µg/mL, respectively, against HepG2 cells) were identified as promising starting points for further optimization studies.
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spelling pubmed-81978552021-06-14 Peptide/β-Peptoid Hybrids with Activity against Vancomycin-Resistant Enterococci: Influence of Hydrophobicity and Structural Features on Antibacterial and Hemolytic Properties Vestergaard, Martin Skive, Bolette Domraceva, Ilona Ingmer, Hanne Franzyk, Henrik Int J Mol Sci Article Infections with enterococci are challenging to treat due to intrinsic resistance to several antibiotics. Especially vancomycin-resistant Enterococcus faecium and Enterococcus faecalis are of considerable concern with a limited number of efficacious therapeutics available. From an initial screening of 20 peptidomimetics, 11 stable peptide/β-peptoid hybrids were found to have antibacterial activity against eight E. faecium and E. faecalis isolates. Microbiological characterization comprised determination of minimal inhibitory concentrations (MICs), probing of synergy with antibiotics in a checkerboard assay, time–kill studies, as well as assessment of membrane integrity. E. faecium isolates proved more susceptible than E. faecalis isolates, and no differences in susceptibility between the vancomycin-resistant (VRE) and -susceptible E. faecium isolates were observed. A test of three peptidomimetics (Ac-[hArg-βNsce](6)-NH(2), Ac-[hArg-βNsce-Lys-βNspe](3)-NH(2) and Oct-[Lys-βNspe](6)-NH(2)) in combination with conventional antibiotics (vancomycin, gentamicin, ciprofloxacin, linezolid, rifampicin or azithromycin) revealed no synergy. The same three potent analogues were found to have a bactericidal effect with a membrane-disruptive mode of action. Peptidomimetics Ac-[hArg-βNsce-Lys-βNspe](3)-NH(2) and Oct-[Lys-βNspe](6)-NH(2) with low MIC values (in the ranges 2–8 µg/mL and 4–16 µg/mL against E. faecium and E. faecalis, respectively) and displaying weak cytotoxic properties (i.e., <10% hemolysis at a ~100-fold higher concentration than their MICs; IC(50) values of 73 and 41 µg/mL, respectively, against HepG2 cells) were identified as promising starting points for further optimization studies. MDPI 2021-05-25 /pmc/articles/PMC8197855/ /pubmed/34070683 http://dx.doi.org/10.3390/ijms22115617 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Vestergaard, Martin
Skive, Bolette
Domraceva, Ilona
Ingmer, Hanne
Franzyk, Henrik
Peptide/β-Peptoid Hybrids with Activity against Vancomycin-Resistant Enterococci: Influence of Hydrophobicity and Structural Features on Antibacterial and Hemolytic Properties
title Peptide/β-Peptoid Hybrids with Activity against Vancomycin-Resistant Enterococci: Influence of Hydrophobicity and Structural Features on Antibacterial and Hemolytic Properties
title_full Peptide/β-Peptoid Hybrids with Activity against Vancomycin-Resistant Enterococci: Influence of Hydrophobicity and Structural Features on Antibacterial and Hemolytic Properties
title_fullStr Peptide/β-Peptoid Hybrids with Activity against Vancomycin-Resistant Enterococci: Influence of Hydrophobicity and Structural Features on Antibacterial and Hemolytic Properties
title_full_unstemmed Peptide/β-Peptoid Hybrids with Activity against Vancomycin-Resistant Enterococci: Influence of Hydrophobicity and Structural Features on Antibacterial and Hemolytic Properties
title_short Peptide/β-Peptoid Hybrids with Activity against Vancomycin-Resistant Enterococci: Influence of Hydrophobicity and Structural Features on Antibacterial and Hemolytic Properties
title_sort peptide/β-peptoid hybrids with activity against vancomycin-resistant enterococci: influence of hydrophobicity and structural features on antibacterial and hemolytic properties
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197855/
https://www.ncbi.nlm.nih.gov/pubmed/34070683
http://dx.doi.org/10.3390/ijms22115617
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