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Antimicrobial and anti-inflammatory activities of chemokine CXCL14-derived antimicrobial peptide and its analogs.

Authors :
Rajasekaran, Ganesan
Dinesh Kumar, S.
Nam, Jiyoung
Jeon, Dasom
Kim, Yangmee
Lee, Chul Won
Park, Il-Seon
Shin, Song Yub
Source :
BBA: Biomembranes. Jan2019, Vol. 1861 Issue 1, p256-267. 12p.
Publication Year :
2019

Abstract

Abstract CXCL14 is a CXC chemokine family that exhibits antimicrobial activity and contains an amphipathic cationic α-helical region in the C-terminus, a characteristic structure of antimicrobial peptides (AMPs). In this study, we designed three analogs of CXCL14 59–75 (named CXCL14-C17) corresponding to the C-terminal α-helix of CXCL14, which displayed potential antimicrobial activity against a wide variety of gram-negative and gram-positive bacteria with minimum inhibitory concentrations of 4−16 μM without mammalian cell toxicity. Furthermore, two CXCL14-C17 analogs (CXCL14-C17-a1 and CXCL14-C17-a3) with improved cell selectivity were engineered by introducing Lys, Arg, or Trp in CXCL14-C17. Additionally, CXCL14-C17 analogs showed much greater synergistic effect (FICI: 0.3125–0.375) with chloramphenicol and ciprofloxacin against multidrug-resistant Pseudomonas aeruginosa (MDRPA) than LL-37 did (FICI: 0.75–1.125). CXCL14-C17 analogs were more active against antibiotic-resistant bacteria including methicillin-resistant Staphylococcus aureus (MRSA), MDRPA, and vancomycin-resistant Enterococcus faecium (VREF) than LL-37 and melittin. In particular, CXCL14-C17-a2 and CXCL14-C17-a3 completely inhibited the biofilm formation at sub-MIC and all of the peptides were able to eliminate pre-formed biofilm as well. Membrane depolarization, flow cytometry, sytox green uptake, ONPG hydrolysis and confocal microscopy revealed the possible target of the native peptide (CXCL14-C17) to likely be intracellular, and the amphipathic designed analogs targeted the bacterial membrane. CXCL14-C17 also showed DNA binding characteristic activity similar to buforin-2. Interestingly, CXCL14-C17-a2 and CXCL14-C17-a3 effectively inhibited the production and expression of nitric oxide (NO), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and monocyte chemoattractant protein (MCP)-1 from lipopolysaccharide (LPS)-stimulated RAW264.7 cells, suggesting that these peptides could be promising anti-inflammatory and antimicrobial agents. Graphical abstract Unlabelled Image Highlights • CXCL14-C17 corresponding to the C-terminal α-helix of a CXC chemokine family CXCL14 and its analogs were designed and synthesized. • CXCL14-C17 displayed potent antimicrobial activity (MIC range: 4−16μM) without mammalian cell toxicity. • The main target of CXCL14-C17 and its analogs is intracellular and bacterial membrane, respectively. • CXCL14-C17 analogs were more active against antibiotic-resistant bacteria including MRSA, MDRPA and VREF than LL-37 and melittin. • CXCL14-C17-a2 and CXCL14-C17-a3 could be promising antimicrobial and anti-inflammatory agents. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00052736
Volume :
1861
Issue :
1
Database :
Academic Search Index
Journal :
BBA: Biomembranes
Publication Type :
Academic Journal
Accession number :
133067690
Full Text :
https://doi.org/10.1016/j.bbamem.2018.06.016