Novel anti-microbial peptide SR-0379 accelerates wound healing via the PI3 kinase/Akt/mTOR pathway

• Published in: PloS one 2014-03, Vol.9 (3), p.e92597
• Main Authors: Tomioka, Hideki, Nakagami, Hironori, Tenma, Akiko, Saito, Yoshimi, Kaga, Toshihiro, Kanamori, Toshihide, Tamura, Nao, Tomono, Kazunori, Kaneda, Yasufumi, Morishita, Ryuichi
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Amino acids; Angiogenesis; Animals; Antibiotics; Antiinfectives and antibacterials; Antimicrobial activity; Antimicrobial agents; Antimicrobial Cationic Peptides - metabolism; Antimicrobial Cationic Peptides - pharmacology; Bacteria; Bacteria - drug effects; Biology and life sciences; Cell culture; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Child development; Colonization; Defects; Diabetes; Diabetes mellitus; Disease Models, Animal; Drug development; Drug resistance; E coli; Endothelial cells; Endothelial Cells - metabolism; Escherichia coli; Fibroblast growth factor 2; Fibroblast Growth Factor 2 - pharmacology; Fibroblast growth factors; Fibroblasts; Fungi; Fungi - drug effects; Gene therapy; Granulation; Growth factors; Humans; Inoculation; Integrins; Kinases; Male; Medicine; Medicine and Health Sciences; Metabolites; Metabolomics; Microbial Sensitivity Tests; Microorganisms; Peptides; Phosphatidylinositol 3-Kinase - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Pseudomonas aeruginosa; Rats; Research and Analysis Methods; Signal Transduction - drug effects; Skin; Staphylococcus aureus; TOR protein; TOR Serine-Threonine Kinases - metabolism; Ulcers; Umbilical vein; University graduates; Wound healing; Wound Healing - drug effects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0092597

We developed a novel cationic antimicrobial peptide, AG30/5C, which demonstrates angiogenic properties similar to those of LL-37 or PR39. However, improvement of its stability and cost efficacy are required for clinical application. Therefore, we examined the metabolites of AG30/5C, which provided the further optimized compound, SR-0379. SR-0379 enhanced the proliferation of human dermal fibroblast cells (NHDFs) via the PI3 kinase-Akt-mTOR pathway through integrin-mediated interactions. Furthermore SR-0379 promoted the tube formation of human umbilical vein endothelial cells (HUVECs) in co-culture with NHDFs. This compound also displays antimicrobial activities against a number of bacteria, including drug-resistant microbes and fungi. We evaluated the effect of SR-0379 in two different would-healing models in rats, the full-thickness defects under a diabetic condition and an acutely infected wound with full-thickness defects and inoculation with Staphylococcus aureus. Treatment with SR-0379 significantly accelerated wound healing when compared to fibroblast growth factor 2 (FGF2). The beneficial effects of SR-0379 on wound healing can be explained by enhanced angiogenesis, granulation tissue formation, proliferation of endothelial cells and fibroblasts and antimicrobial activity. These results indicate that SR-0379 may have the potential for drug development in wound repair, even under especially critical colonization conditions.