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

PLoS One. 2014 Mar 27;9(3):e92597. doi: 10.1371/journal.pone.0092597. eCollection 2014.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimicrobial Cationic Peptides / metabolism
  • Antimicrobial Cationic Peptides / pharmacology*
  • Bacteria / drug effects
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Endothelial Cells / metabolism
  • Fibroblast Growth Factor 2 / pharmacology
  • Fungi / drug effects
  • Humans
  • Male
  • Metabolomics
  • Microbial Sensitivity Tests
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats
  • Signal Transduction / drug effects*
  • TOR Serine-Threonine Kinases / metabolism*
  • Wound Healing / drug effects*

Substances

  • AG30 peptide
  • Antimicrobial Cationic Peptides
  • SR-0379
  • Fibroblast Growth Factor 2
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases

Grants and funding

This study was supported by a Health Labour Sciences Research Grant in Japan, and partially funded by AnGes MG. No additional funding was received for this study. Hideki Tomioka, Akiko Tenma, Yoshimi Saito, Toshihiro Kaga, Toshihide Kanamori and Nao Tamura are employees of AnGes MG. The funder provided support in the form of salaries for authors, but did not have any additional role in the study design, data collection andanalysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the “Author Contributions” section.