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Development of a novel short 12-meric papiliocin-derived peptide that is effective against Gram-negative sepsis
The development of novel peptide antibiotics with potent activity against multidrug-resistant Gram-negative bacteria and anti-septic activity is urgently needed. In this study, we designed short, 12-meric antimicrobial peptides by substituting amino acids from the N-terminal 12 residues of the papil...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405874/ https://www.ncbi.nlm.nih.gov/pubmed/30846839 http://dx.doi.org/10.1038/s41598-019-40577-8 |
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author | Kim, Jieun Jacob, Binu Jang, Mihee Kwak, Chulhee Lee, Yeongjoon Son, Kkabi Lee, Sujin Jung, In Duk Jeong, Myeong Seon Kwon, Seung-Hae Kim, Yangmee |
author_facet | Kim, Jieun Jacob, Binu Jang, Mihee Kwak, Chulhee Lee, Yeongjoon Son, Kkabi Lee, Sujin Jung, In Duk Jeong, Myeong Seon Kwon, Seung-Hae Kim, Yangmee |
author_sort | Kim, Jieun |
collection | PubMed |
description | The development of novel peptide antibiotics with potent activity against multidrug-resistant Gram-negative bacteria and anti-septic activity is urgently needed. In this study, we designed short, 12-meric antimicrobial peptides by substituting amino acids from the N-terminal 12 residues of the papiliocin (Pap12-1) peptide to alter cationicity and amphipathicity and improve antibacterial activity and bacterial membrane interactions. Pap12-6, with an amphipathic α-helical structure and Trp(12) at the C-terminus, showed broad-spectrum antibacterial activity, especially against multidrug-resistant Gram-negative bacteria. Dye leakage, membrane depolarization, and electron microscopy data proved that Pap12-6 kills bacteria by permeabilizing the bacterial membrane. Additionally, Pap12-6 significantly reduced the secretion of NO, TNF-α, and IL-6 and secreted alkaline phosphatase reporter gene activity confirmed that Pap12-6 shows anti-inflammatory activity via a TLR4-mediated NF-κB signaling pathway. In a mouse sepsis model, Pap12-6 significantly improved survival, reduced bacterial growth in organs, and reduced LPS and inflammatory cytokine levels in the serum and organs. Pap12-6 showed minimal cytotoxicity towards mammalian cells and controlled liver and kidney damage, proving its high bacterial selectivity. Our results suggest that Pap12-6 is a promising peptide antibiotic for the therapeutic treatment of Gram-negative sepsis via dual bactericidal and immunomodulatory effects on the host. |
format | Online Article Text |
id | pubmed-6405874 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-64058742019-03-11 Development of a novel short 12-meric papiliocin-derived peptide that is effective against Gram-negative sepsis Kim, Jieun Jacob, Binu Jang, Mihee Kwak, Chulhee Lee, Yeongjoon Son, Kkabi Lee, Sujin Jung, In Duk Jeong, Myeong Seon Kwon, Seung-Hae Kim, Yangmee Sci Rep Article The development of novel peptide antibiotics with potent activity against multidrug-resistant Gram-negative bacteria and anti-septic activity is urgently needed. In this study, we designed short, 12-meric antimicrobial peptides by substituting amino acids from the N-terminal 12 residues of the papiliocin (Pap12-1) peptide to alter cationicity and amphipathicity and improve antibacterial activity and bacterial membrane interactions. Pap12-6, with an amphipathic α-helical structure and Trp(12) at the C-terminus, showed broad-spectrum antibacterial activity, especially against multidrug-resistant Gram-negative bacteria. Dye leakage, membrane depolarization, and electron microscopy data proved that Pap12-6 kills bacteria by permeabilizing the bacterial membrane. Additionally, Pap12-6 significantly reduced the secretion of NO, TNF-α, and IL-6 and secreted alkaline phosphatase reporter gene activity confirmed that Pap12-6 shows anti-inflammatory activity via a TLR4-mediated NF-κB signaling pathway. In a mouse sepsis model, Pap12-6 significantly improved survival, reduced bacterial growth in organs, and reduced LPS and inflammatory cytokine levels in the serum and organs. Pap12-6 showed minimal cytotoxicity towards mammalian cells and controlled liver and kidney damage, proving its high bacterial selectivity. Our results suggest that Pap12-6 is a promising peptide antibiotic for the therapeutic treatment of Gram-negative sepsis via dual bactericidal and immunomodulatory effects on the host. Nature Publishing Group UK 2019-03-07 /pmc/articles/PMC6405874/ /pubmed/30846839 http://dx.doi.org/10.1038/s41598-019-40577-8 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Kim, Jieun Jacob, Binu Jang, Mihee Kwak, Chulhee Lee, Yeongjoon Son, Kkabi Lee, Sujin Jung, In Duk Jeong, Myeong Seon Kwon, Seung-Hae Kim, Yangmee Development of a novel short 12-meric papiliocin-derived peptide that is effective against Gram-negative sepsis |
title | Development of a novel short 12-meric papiliocin-derived peptide that is effective against Gram-negative sepsis |
title_full | Development of a novel short 12-meric papiliocin-derived peptide that is effective against Gram-negative sepsis |
title_fullStr | Development of a novel short 12-meric papiliocin-derived peptide that is effective against Gram-negative sepsis |
title_full_unstemmed | Development of a novel short 12-meric papiliocin-derived peptide that is effective against Gram-negative sepsis |
title_short | Development of a novel short 12-meric papiliocin-derived peptide that is effective against Gram-negative sepsis |
title_sort | development of a novel short 12-meric papiliocin-derived peptide that is effective against gram-negative sepsis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405874/ https://www.ncbi.nlm.nih.gov/pubmed/30846839 http://dx.doi.org/10.1038/s41598-019-40577-8 |
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