Antibacterial activities of amphiphilic cyclic cell-penetrating peptides against multidrug-resistant pathogens
Date of Original Version
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.
Publication Title, e.g., Journal
Oh, Donghoon, Sun, Amir Nasrolahi Shirazi, Kerry L. Laplante, David C. Rowley, and Keykavous Parang. "Antibacterial activities of amphiphilic cyclic cell-penetrating peptides against multidrug-resistant pathogens." Molecular Pharmaceutics 11, 10 (2014): 3528-3536. doi: 10.1021/mp5003027.