LL-37-derived membrane-active FK-13 analogs possessing cell selectivity, anti-biofilm activity and synergy with chloramphenicol and anti-inflammatory activity

• Published in: Biochimica et biophysica acta. Biomembranes Vol. 1859; no. 5; pp. 722 - 733
• Main Authors: Rajasekaran, Ganesan, Kim, Eun Young, Shin, Song Yub
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-05-2017
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; Anti-biofilm activity; Anti-Infective Agents - pharmacology; Anti-inflammatory activity; Anti-Inflammatory Agents - pharmacology; Antimicrobial Cationic Peptides - pharmacology; Biofilms - drug effects; Cell selectivity; Cells, Cultured; Chloramphenicol - pharmacology; Drug Design; Drug Synergism; Humans; Methicillin-Resistant Staphylococcus aureus - drug effects; Mice; Short α-helical antimicrobial peptides; Synergistic effect; Cell selectivity; Anti-inflammatory activity; Synergistic effect; Anti-biofilm activity; Short α-helical antimicrobial peptides
• ISSN: 0005-2736; 1879-2642
• DOI: 10.1016/j.bbamem.2017.01.037

Although the human-derived antimicrobial peptide (AMP) LL-37 has potent antimicrobial and anti-inflammatory activities, its therapeutic application is limited by its low cell selectivity and high production cost due to its large size. To overcome these problems, we tried to develop novel LL-37-derived short α-helical AMPs with improved cell selectivity and without a significant loss of anti-inflammatory activity relative to that of parental LL-37. Using amino acid substitution, we designed and synthesized a series of FK13 analogs based on the sequence of the 13-meric short FK13 peptide (residues 17–29 of LL-37) that has been identified as the region responsible for the antimicrobial activity of LL-37. Among the designed FK13 analogs, FK-13-a1 and FK-13-a7 showed high cell selectivity and retained the anti-inflammatory activity. The therapeutic index (a measure of cell selectivity) of FK-13-a1 and FK-13-a7 was 6.3- and 2.3-fold that of parental LL-37, respectively. Furthermore, FK-13-a1 and FK-13-a7 displayed more potent antimicrobial activity against antibiotic-resistant bacteria including MRSA, MDRPA, and VREF, than did LL-37. In addition, FK-13-a1 and FK-13-a7 exhibited greater synergistic effects with chloramphenicol against MRSA and MDRPA and were more effective anti-biofilm agents against MDRPA than LL-37 was. Moreover, FK-13-a1 and FK-13-a7 maintained their activities in the presence of physiological salts and human serum. SYTOX green uptake, membrane depolarization and killing kinetics revealed that FK13-a1 and FK13-a7 kills microbial cells by permeabilizing the cell membrane and damaging membrane integrity. Taken together, our results suggest that FK13-a1 and FK13-a7 can be developed as novel antimicrobial/anti-inflammatory agents.
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•K13-a1 and FK13-a7 improved cell selectivity without a significant loss of anti-inflammatory activity.•FK13-a1 and FK13-a7 showed potent antimicrobial activity against antibiotic-resistant bacteria.•FK13-a1 and FK13-a7 showed anti-biofilm activity and synergistic effect with chloramphenicol.•FK13-a1 and FK13-a7 can be developed into novel antimicrobial/anti-inflammatory agents.