Antibacterial activities of amphiphilic cyclic cell-penetrating peptides against multidrug-resistant pathogens

Donghoon Oh, Jiadong Sun, Amir Nasrolahi Shirazi, Kerry L. Laplante, David C. Rowley, Keykavous Parang

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


Multidrug-resistant pathogens have become a major public health concern. There is a great need for the development of novel antibiotics with alternative mechanisms of action for the treatment of life-threatening bacterial infections. Antimicrobial peptides, a major class of antibacterial agents, share amphiphilicity and cationic structural properties with cell-penetrating peptides (CPPs). Herein, several amphiphilic cyclic CPPs and their analogues were synthesized and exhibited potent antibacterial activities against multidrug-resistant pathogens. Among all the peptides, cyclic peptide [R4W4] (1) showed the most potent antibacterial activity against methicillin-resistant Staphylococcus aureus [MRSA, exhibiting a minimal inhibitory concentration (MIC) of 2.67 μg/mL]. Cyclic [R4W4] and the linear counterpart R4W4 exhibited MIC values of 42.8 and 21.7 μg/mL, respectively, against Pseudomonas aeruginosa. In eukaryotic cells, peptide 1 exhibited the expected cell penetrating properties and showed >84% cell viability at a concentration of 15 μM (20.5 μg/mL) in three different human cell lines. Twenty-four hour time-kill studies evaluating [R4W4] with 2 times the MIC in combination with tetracycline demonstrated bactericidal activity at 4 and 8 times the MIC of tetracycline against MRSA (MIC = 0.5 μg/mL) and 2-8 times the MIC against Escherichia coli (MIC = 2 μg/mL). This study suggests that when amphiphilic cyclic CPPs are used in combination with an antibiotic such as tetracycline, they provide significant benefit against multidrug-resistant pathogens when compared with the antibiotic alone.

Original languageEnglish (US)
Pages (from-to)3528-3536
Number of pages9
JournalMolecular Pharmaceutics
Issue number10
StatePublished - Oct 6 2014
Externally publishedYes


  • antimicrobial peptide
  • cell-penetrating peptide
  • combination
  • drug delivery
  • methicillin-resistant Staphylococcus aureus

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Molecular Medicine
  • Drug Discovery
  • General Medicine


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