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Structure–Activity Study, Characterization, and Mechanism of Action of an Antimicrobial Peptoid D2 and Its d- and l-Peptide Analogues

Methicillin-resistant Staphylococcus pseudintermedius (MRSP) constitutes an emerging health problem for companion animals in veterinary medicine. Therefore, discovery of novel antimicrobial agents for treatment of Staphylococcus-associated canine infections is urgently needed to reduce use of human...

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Autores principales: Greco, Ines, Hansen, Johannes E., Jana, Bimal, Molchanova, Natalia, Oddo, Alberto, Thulstrup, Peter W., Damborg, Peter, Guardabassi, Luca, Hansen, Paul R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470533/
https://www.ncbi.nlm.nih.gov/pubmed/30901860
http://dx.doi.org/10.3390/molecules24061121
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author Greco, Ines
Hansen, Johannes E.
Jana, Bimal
Molchanova, Natalia
Oddo, Alberto
Thulstrup, Peter W.
Damborg, Peter
Guardabassi, Luca
Hansen, Paul R.
author_facet Greco, Ines
Hansen, Johannes E.
Jana, Bimal
Molchanova, Natalia
Oddo, Alberto
Thulstrup, Peter W.
Damborg, Peter
Guardabassi, Luca
Hansen, Paul R.
author_sort Greco, Ines
collection PubMed
description Methicillin-resistant Staphylococcus pseudintermedius (MRSP) constitutes an emerging health problem for companion animals in veterinary medicine. Therefore, discovery of novel antimicrobial agents for treatment of Staphylococcus-associated canine infections is urgently needed to reduce use of human antibiotics in veterinary medicine. In the present work, we characterized the antimicrobial activity of the peptoid D2 against S. pseudintermedius and Pseudomonas aeruginosa, which is another common integumentary pathogen in dogs. Furthermore, we performed a structure–activity relationship study of D2, which included 19 peptide/peptoid analogs. Our best compound D2D, an all d-peptide analogue, showed potent minimum inhibitory concentrations (MICs) against canine S. pseudintermedius (2–4 µg/mL) and P. aeruginosa (4 µg/mL) isolates as well as other selected dog pathogens (2–16 µg/mL). Time–kill assays demonstrated that D2D was able to inhibit MRSP in 30 min at 1× MIC, significantly faster than D2. Our results suggest that at high concentrations D2D is rapidly lysing the bacterial membrane while D2 is inhibiting macromolecular synthesis. We probed the mechanism of action at sub-MIC concentrations of D2, D2D, the l-peptide analog and its retro analog by a macromolecular biosynthesis assay and fluorescence spectroscopy. Our data suggest that at sub-MIC concentrations D2D is membrane inactive and primarily works by cell wall inhibition, while the other compounds mainly act on the bacterial membrane.
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spelling pubmed-64705332019-04-26 Structure–Activity Study, Characterization, and Mechanism of Action of an Antimicrobial Peptoid D2 and Its d- and l-Peptide Analogues Greco, Ines Hansen, Johannes E. Jana, Bimal Molchanova, Natalia Oddo, Alberto Thulstrup, Peter W. Damborg, Peter Guardabassi, Luca Hansen, Paul R. Molecules Article Methicillin-resistant Staphylococcus pseudintermedius (MRSP) constitutes an emerging health problem for companion animals in veterinary medicine. Therefore, discovery of novel antimicrobial agents for treatment of Staphylococcus-associated canine infections is urgently needed to reduce use of human antibiotics in veterinary medicine. In the present work, we characterized the antimicrobial activity of the peptoid D2 against S. pseudintermedius and Pseudomonas aeruginosa, which is another common integumentary pathogen in dogs. Furthermore, we performed a structure–activity relationship study of D2, which included 19 peptide/peptoid analogs. Our best compound D2D, an all d-peptide analogue, showed potent minimum inhibitory concentrations (MICs) against canine S. pseudintermedius (2–4 µg/mL) and P. aeruginosa (4 µg/mL) isolates as well as other selected dog pathogens (2–16 µg/mL). Time–kill assays demonstrated that D2D was able to inhibit MRSP in 30 min at 1× MIC, significantly faster than D2. Our results suggest that at high concentrations D2D is rapidly lysing the bacterial membrane while D2 is inhibiting macromolecular synthesis. We probed the mechanism of action at sub-MIC concentrations of D2, D2D, the l-peptide analog and its retro analog by a macromolecular biosynthesis assay and fluorescence spectroscopy. Our data suggest that at sub-MIC concentrations D2D is membrane inactive and primarily works by cell wall inhibition, while the other compounds mainly act on the bacterial membrane. MDPI 2019-03-21 /pmc/articles/PMC6470533/ /pubmed/30901860 http://dx.doi.org/10.3390/molecules24061121 Text en © 2019 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
Greco, Ines
Hansen, Johannes E.
Jana, Bimal
Molchanova, Natalia
Oddo, Alberto
Thulstrup, Peter W.
Damborg, Peter
Guardabassi, Luca
Hansen, Paul R.
Structure–Activity Study, Characterization, and Mechanism of Action of an Antimicrobial Peptoid D2 and Its d- and l-Peptide Analogues
title Structure–Activity Study, Characterization, and Mechanism of Action of an Antimicrobial Peptoid D2 and Its d- and l-Peptide Analogues
title_full Structure–Activity Study, Characterization, and Mechanism of Action of an Antimicrobial Peptoid D2 and Its d- and l-Peptide Analogues
title_fullStr Structure–Activity Study, Characterization, and Mechanism of Action of an Antimicrobial Peptoid D2 and Its d- and l-Peptide Analogues
title_full_unstemmed Structure–Activity Study, Characterization, and Mechanism of Action of an Antimicrobial Peptoid D2 and Its d- and l-Peptide Analogues
title_short Structure–Activity Study, Characterization, and Mechanism of Action of an Antimicrobial Peptoid D2 and Its d- and l-Peptide Analogues
title_sort structure–activity study, characterization, and mechanism of action of an antimicrobial peptoid d2 and its d- and l-peptide analogues
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470533/
https://www.ncbi.nlm.nih.gov/pubmed/30901860
http://dx.doi.org/10.3390/molecules24061121
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