title: De novo design and synthesis of ultra-short peptidomimetic antibiotics having dual antimicrobial and anti-inflammatory activities.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, Chung-Buk, Republic of Korea.
authors.forename: Ravichandran N
authors.initials: RN
authors.lastname: Murugan
authors.forename: Binu
authors.initials: B
authors.lastname: Jacob
authors.forename: Mija
authors.initials: M
authors.lastname: Ahn
authors.forename: Eunha
authors.initials: E
authors.lastname: Hwang
authors.forename: Hoik
authors.initials: H
authors.lastname: Sohn
authors.forename: Hyo-Nam
authors.initials: HN
authors.lastname: Park
authors.forename: Eunjung
authors.initials: E
authors.lastname: Lee
authors.forename: Ji-Hyung
authors.initials: JH
authors.lastname: Seo
authors.forename: Chaejoon
authors.initials: C
authors.lastname: Cheong
authors.forename: Ky-Youb
authors.initials: KY
authors.lastname: Nam
authors.forename: Jae-Kyung
authors.initials: JK
authors.lastname: Hyun
authors.forename: Ki-Woong
authors.initials: KW
authors.lastname: Jeong
authors.forename: Yangmee
authors.initials: Y
authors.lastname: Kim
authors.forename: Song Yub
authors.initials: SY
authors.lastname: Shin
authors.forename: Jeong Kyu
authors.initials: JK
authors.lastname: Bang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D015195:Drug Design; D006461:Hemolysis / Q000187:drug effects; D006838:Hydrocarbons / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D008564:Membrane Potentials / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D018716:Molecular Mimicry; D015394:Molecular Structure; D059748:Proteolysis; D055672:Static Electricity
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D000893:Anti-Inflammatory Agents; D023181:Antimicrobial Cationic Peptides; D006838:Hydrocarbons