De Novo Design and Synthesis of Ultra-Short Peptidomimetic Antibiotics Having Dual Antimicrobial and Anti-Inflammatory Activities

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dc.creatorMurugan, Ravichandran N.en
dc.creatorJacob, Binuen
dc.creatorAhn, Mijaen
dc.creatorHwang, Eunhaen
dc.creatorSohn, Hoiken
dc.creatorPark, Hyo-Namen
dc.creatorLee, Eunjungen
dc.creatorSeo, Ji-Hyungen
dc.creatorCheong, Chaejoonen
dc.creatorNam, Ky-Youben
dc.creatorHyun, Jae-Kyungen
dc.creatorJeong, Ki-Woongen
dc.creatorKim, Yangmeeen
dc.creatorShin, Song Yuben
dc.creatorBang, Jeong Kyuen
dc.date.accessioned2014-12-15T17:10:44Zen
dc.date.available2014-12-15T17:10:44Zen
dc.date.issued2013-11-26en
dc.descriptionRavichandran N. Murugan, Mija Ahn, Eunha Hwang, Ji-Hyung Seo, Chaejoon Cheong, Jeong Kyu Bang, Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, Chung-Buk, Republic of Koreaen
dc.descriptionBinu Jacob, Song Yub Shin, Department of Bio-Materials, Graduate School and Department of Cellular and Molecular Medicine, School of Medicine, Chosun University, Gwangju, Republic of Koreaen
dc.descriptionHoik Sohn, Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas, United States of Americaen
dc.descriptionHyo-Nam Park, Jae-Kyung Hyun, Division of Electron Microscopic Research, Korea Basic Science Institute, Daejeon, Republic of Koreaen
dc.descriptionEunjung Lee, Ki-Woong Jeong, Yangmee Kim, Department of Bioscience and Biotechnology, Institute of SMART Biotechnology, Konkuk University, Seoul, Republic of Koreaen
dc.descriptionKy-Youb Nam, Bioinformatics and Molecular Design Research Center, Yonsei University Research Complex, Seoul, Republic of Koreaen
dc.description.abstractBackground: 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.en
dc.description.catalogingnoteEmail: bangjk@kbsi.re.kr (JKB)en
dc.description.catalogingnoteEmail: syshin@chosun.ac.kr (SYS)en
dc.description.departmentChemistryen
dc.description.departmentBiochemistryen
dc.description.sponsorshipThis work was supported in part by the Korea Basic Science Institute's research program grants T33418 (J.K.B) and T33518 (J-k.H.), and the Korea Research Foundation, funded by the Korean Government (KRF-2011-0009039 to S.Y.S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en
dc.identifier.Filenamejournal.pone.0080025.pdfen
dc.identifier.citationMurugan RN, Jacob B, Ahn M, Hwang E, Sohn H, et al. (2013) De Novo Design and Synthesis of Ultra-Short Peptidomimetic Antibiotics Having Dual Antimicrobial and Anti-Inflammatory Activities. PLoS ONE 8(11): e80025. doi:10.1371/journal.pone.0080025en
dc.identifier.doiDOI: 10.1371/journal.pone.0080025en
dc.identifier.urihttp://hdl.handle.net/2152/27923en
dc.language.isoEnglishen
dc.publisherPLOS Oneen
dc.rightsAdministrative deposit of works to UT Digital Repository: This works author(s) is or was a University faculty member, student or staff member; this article is already available through open access at http://www.plosone.org. The public license is specified as CC-BY: http://creativecommons.org/licenses/by/4.0/. The library makes the deposit as a matter of fair use (for scholarly, educational, and research purposes), and to preserve the work and further secure public access to the works of the University.en
dc.subjectantimicrobialsen
dc.subjectbacteriaen
dc.subjectcell membranesen
dc.subjectmatrix-assisted laser desoption ionizationen
dc.subjectmembrane potentialen
dc.subjectpeptide synthesisen
dc.subjectreversed-phase high performance liquiden
dc.subjectstaphylococcus aureusen
dc.titleDe Novo Design and Synthesis of Ultra-Short Peptidomimetic Antibiotics Having Dual Antimicrobial and Anti-Inflammatory Activitiesen
dc.typeArticleen

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