Aurein-Derived Antimicrobial Peptides Formulated with Pegylated Phospholipid Micelles to Target Methicillin-Resistant Staphylococcus aureus Skin Infections

Prashant Kumar, Daniel Pletzer, Evan F. Haney, Negin Rahanjam, John T.J. Cheng, Marty Yue, Waleed Aljehani, Robert Hancock, Jayachandran N. Kizhakkedathu, Suzana K. Straus

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Antimicrobial peptides have been the focus of considerable research; however, issues associated with toxicity and aggregation have the potential to limit clinical applications. Here, a derivative of a truncated version of aurein 2.2 (aurein 2.2Δ3), namely peptide 73, was investigated, along with its d-amino acid counterpart (D-73) and a retro-inverso version (RI-73). A version that incorporated a cysteine residue to the C-terminus (73c) was also generated, as this form is required to covalently attach antimicrobial peptides to polymers (e.g., polyethylene glycol (PEG) or hyperbranched polyglycerol (HPG)). The antimicrobial activity of the 73-derived peptides was enhanced 2- to 8-fold, and all the derivatives eradicated preformed Staphylococcus aureus biofilms. Formulation of the peptides with compatible polyethylene glycol (PEG)-modified phospholipid micelles alleviated toxicity toward human cells and reduced aggregation. When evaluated in vivo, the unformulated d-enantiomers aggregated when injected under the skin of mice, but micelle encapsulated peptides were well absorbed. Pegylated micelle formulated peptides were investigated for their potential as therapeutic agents for treating high-density infections in a murine cutaneous abscess model. Formulated peptide 73 reduced abscess size by 36% and bacterial loads by 2.2-fold compared to the parent peptide aurein 2.2Δ3. Micelle encapsulated peptides 73c and D-73 exhibited superior activity, further reducing abscess sizes by 85% and 63% and lowering bacterial loads by 510- and 9-fold compared to peptide 73.

LanguageEnglish
Pages443-453
Number of pages11
JournalACS Infectious Diseases
Volume5
Issue number3
DOIs
Publication statusPublished - 8 Mar 2019
Externally publishedYes

Keywords

  • DSPE-PEG2000
  • MRSA
  • abscess
  • aggregation
  • biofilm
  • toxicity

ASJC Scopus subject areas

  • Infectious Diseases

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