title: Pyrazole derived ultra-short antimicrobial peptidomimetics with potent anti-biofilm activity.
abstract: In this study, we report on the first chemical synthesis of ultra-short pyrazole-arginine based antimicrobial peptidomimetics derived from the newly synthesized N-alkyl/aryl pyrazole amino acids. Through the systematic tuning of hydrophobicity, charge, and peptide length, we identified the shortest peptide Py11 with the most potent antimicrobial activity. Py11 displayed greater antimicrobial activity against antibiotic-resistant bacteria, including MRSA, MDRPA, and VREF, which was approximately 2-4 times higher than that of melittin. Besides its higher selectivity (therapeutic index) toward bacterial cells than LL-37, Py11 showed highly increased proteolytic stability against trypsin digestion and maintained its antimicrobial activity in the presence of physiological salts. Interestingly, Py11 exhibited higher anti-biofilm activity against MDRPA compared to LL-37. The results from fluorescence spectroscopy and transmission electron microscopy (TEM) suggested that Py11 kills bacterial cells possibly by integrity disruption damaging the cell membrane, leading to the cytosol leakage and eventual cell lysis. Furthermore, Py11 displayed significant anti-inflammatory (endotoxin-neutralizing) activity by inhibiting LPS-induced production of nitric oxide (NO) and TNF-α. Collectively, our results suggest that Py11 may serve as a model compound for the design of antimicrobial and antisepsis agents.
authors.affiliation: Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, Chung-Buk, 363-883, Republic of Korea.
authors.forename: Mija
authors.initials: M
authors.lastname: Ahn
authors.affiliation: Molecular Embryology Laboratory, Department of Animal Sciences, Chungbuk National University, Chung-Buk, 361-763, Republic of Korea.
authors.forename: Pethaiah
authors.initials: P
authors.lastname: Gunasekaran
authors.affiliation: Department of Medical Science, Graduate School and Department of Cellular & Molecular Medicine, School of Medicine, Chosun University, Gwangju, 501-759, Republic of Korea.
authors.forename: Ganesan
authors.initials: G
authors.lastname: Rajasekaran
authors.affiliation: Department of Medical Science, Graduate School and Department of Cellular & Molecular Medicine, School of Medicine, Chosun University, Gwangju, 501-759, Republic of Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chungbuk National University, Chungbuk, 361-763, Republic of Korea.
authors.forename: Soo-Jae
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Biomedical Omics Group, Korea Basic Science Institute, Ochang, Chung-Buk, 363-883, Republic of Korea.
authors.forename: Geul
authors.initials: G
authors.lastname: Bang
authors.affiliation: Biomedical Omics Group, Korea Basic Science Institute, Ochang, Chung-Buk, 363-883, Republic of Korea.
authors.forename: Kun
authors.initials: K
authors.lastname: Cho
authors.affiliation: Division of Electron Microscopic Research, Korea Basic Science Institute, 113 Gwahakro, Daejeon, 305-333, Republic of Korea.
authors.forename: Jae-Kyung
authors.initials: JK
authors.lastname: Hyun
authors.affiliation: Division of Electron Microscopic Research, Korea Basic Science Institute, 113 Gwahakro, Daejeon, 305-333, Republic of Korea; Department of Chemistry, Chungnam National University, Daejeon, 305-764, Republic of Korea.
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Korea University, 2511 Sejong-Ro, Sejong, 30019, Republic of Korea.
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Jeon
authors.affiliation: Molecular Embryology Laboratory, Department of Animal Sciences, Chungbuk National University, Chung-Buk, 361-763, Republic of Korea.
authors.forename: Nam-Hyung
authors.initials: NH
authors.lastname: Kim
authors.affiliation: Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, Chung-Buk, 363-883, Republic of Korea; Department of Bio-analytical Science, University of Science & Technology, Daejeon, 34113, Republic of Korea.
authors.forename: Eun Kyoung
authors.initials: EK
authors.lastname: Ryu
authors.affiliation: Department of Medical Science, Graduate School and Department of Cellular & Molecular Medicine, School of Medicine, Chosun University, Gwangju, 501-759, Republic of Korea. Electronic address: syshin@chosun.ac.kr.
authors.forename: Song Yub
authors.initials: SY
authors.lastname: Shin
authors.affiliation: Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, Chung-Buk, 363-883, Republic of Korea; Department of Bio-analytical Science, University of Science & Technology, Daejeon, 34113, Republic of Korea. Electronic address: bangjk@kbsi.re.kr.
authors.forename: Jeong Kyu
authors.initials: JK
authors.lastname: Bang
mesh_terms: D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D018441:Biofilms / Q000187:drug effects*; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D046529:Microscopy, Electron, Transmission; D015394:Molecular Structure; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D057786:Peptidomimetics; D011720:Pyrazoles
keywords: Anti-biofilm activity; Antimicrobial activity; Bacterial killing mechanism; Pyrazole-derived amino acids; Ultra-short peptidomimetics