De novo design and synthesis of ultra-short peptidomimetic antibiotics having dual antimicrobial and anti-inflammatory activities.
BACKGROUND: Much attention has been focused on the design and synthesis of potent, cationic antimicrobial peptides (AMPs) that possess both antimicrobial and anti-inflammatory activities. However, their development into therapeutic agents has been limited mainly due to their large size (12 to 50 res...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3841161?pdf=render |
| _version_ | 1811279076062658560 |
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| author | Ravichandran N Murugan Binu Jacob Mija Ahn Eunha Hwang Hoik Sohn Hyo-Nam Park Eunjung Lee Ji-Hyung Seo Chaejoon Cheong Ky-Youb Nam Jae-Kyung Hyun Ki-Woong Jeong Yangmee Kim Song Yub Shin Jeong Kyu Bang |
| author_facet | Ravichandran N Murugan Binu Jacob Mija Ahn Eunha Hwang Hoik Sohn Hyo-Nam Park Eunjung Lee Ji-Hyung Seo Chaejoon Cheong Ky-Youb Nam Jae-Kyung Hyun Ki-Woong Jeong Yangmee Kim Song Yub Shin Jeong Kyu Bang |
| author_sort | Ravichandran N Murugan |
| collection | DOAJ |
| description | BACKGROUND: Much attention has been focused on the design and synthesis of potent, cationic antimicrobial peptides (AMPs) that possess both antimicrobial and anti-inflammatory activities. However, their development into therapeutic agents has been limited mainly due to their large size (12 to 50 residues in length) and poor protease stability. METHODOLOGY/PRINCIPAL FINDINGS: In an attempt to overcome the issues described above, a set of ultra-short, His-derived antimicrobial peptides (HDAMPs) has been developed for the first time. Through systematic tuning of pendant hydrophobic alkyl tails at the N(π)- and N(τ)-positions on His, and the positive charge of Arg, much higher prokaryotic selectivity was achieved, compared to human AMP LL-37. Additionally, the most potent HDAMPs showed promising dual antimicrobial and anti-inflammatory activities, as well as anti-methicillin-resistant Staphylococcus aureus (MRSA) activity and proteolytic resistance. Our results from transmission electron microscopy, membrane depolarization, confocal laser-scanning microscopy, and calcein-dye leakage experiments propose that HDAMP-1 kills microbial cells via dissipation of the membrane potential by forming pore/ion channels on bacterial cell membranes. CONCLUSION/SIGNIFICANCE: The combination of the ultra-short size, high-prokaryotic selectivity, potent anti-MRSA activity, anti-inflammatory activity, and proteolytic resistance of the designed HDAMP-1, -3, -5, and -6 makes these molecules promising candidates for future antimicrobial therapeutics. |
| first_indexed | 2024-04-13T00:48:17Z |
| format | Article |
| id | doaj.art-f3a8b3ccce4f4534a7014ee4372678ec |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T00:48:17Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-f3a8b3ccce4f4534a7014ee4372678ec2022-12-22T03:09:57ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-01811e8002510.1371/journal.pone.0080025De novo design and synthesis of ultra-short peptidomimetic antibiotics having dual antimicrobial and anti-inflammatory activities.Ravichandran N MuruganBinu JacobMija AhnEunha HwangHoik SohnHyo-Nam ParkEunjung LeeJi-Hyung SeoChaejoon CheongKy-Youb NamJae-Kyung HyunKi-Woong JeongYangmee KimSong Yub ShinJeong Kyu BangBACKGROUND: Much attention has been focused on the design and synthesis of potent, cationic antimicrobial peptides (AMPs) that possess both antimicrobial and anti-inflammatory activities. However, their development into therapeutic agents has been limited mainly due to their large size (12 to 50 residues in length) and poor protease stability. METHODOLOGY/PRINCIPAL FINDINGS: In an attempt to overcome the issues described above, a set of ultra-short, His-derived antimicrobial peptides (HDAMPs) has been developed for the first time. Through systematic tuning of pendant hydrophobic alkyl tails at the N(π)- and N(τ)-positions on His, and the positive charge of Arg, much higher prokaryotic selectivity was achieved, compared to human AMP LL-37. Additionally, the most potent HDAMPs showed promising dual antimicrobial and anti-inflammatory activities, as well as anti-methicillin-resistant Staphylococcus aureus (MRSA) activity and proteolytic resistance. Our results from transmission electron microscopy, membrane depolarization, confocal laser-scanning microscopy, and calcein-dye leakage experiments propose that HDAMP-1 kills microbial cells via dissipation of the membrane potential by forming pore/ion channels on bacterial cell membranes. CONCLUSION/SIGNIFICANCE: The combination of the ultra-short size, high-prokaryotic selectivity, potent anti-MRSA activity, anti-inflammatory activity, and proteolytic resistance of the designed HDAMP-1, -3, -5, and -6 makes these molecules promising candidates for future antimicrobial therapeutics.http://europepmc.org/articles/PMC3841161?pdf=render |
| spellingShingle | Ravichandran N Murugan Binu Jacob Mija Ahn Eunha Hwang Hoik Sohn Hyo-Nam Park Eunjung Lee Ji-Hyung Seo Chaejoon Cheong Ky-Youb Nam Jae-Kyung Hyun Ki-Woong Jeong Yangmee Kim Song Yub Shin Jeong Kyu Bang De novo design and synthesis of ultra-short peptidomimetic antibiotics having dual antimicrobial and anti-inflammatory activities. PLoS ONE |
| title | De novo design and synthesis of ultra-short peptidomimetic antibiotics having dual antimicrobial and anti-inflammatory activities. |
| title_full | De novo design and synthesis of ultra-short peptidomimetic antibiotics having dual antimicrobial and anti-inflammatory activities. |
| title_fullStr | De novo design and synthesis of ultra-short peptidomimetic antibiotics having dual antimicrobial and anti-inflammatory activities. |
| title_full_unstemmed | De novo design and synthesis of ultra-short peptidomimetic antibiotics having dual antimicrobial and anti-inflammatory activities. |
| title_short | De novo design and synthesis of ultra-short peptidomimetic antibiotics having dual antimicrobial and anti-inflammatory activities. |
| title_sort | de novo design and synthesis of ultra short peptidomimetic antibiotics having dual antimicrobial and anti inflammatory activities |
| url | http://europepmc.org/articles/PMC3841161?pdf=render |
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