title: Antibacterial activities of amphiphilic cyclic cell-penetrating peptides against multidrug-resistant pathogens.
abstract: 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.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island , Kingston, Rhode Island 02881, United States.
authors.forename: Donghoon
authors.initials: D
authors.lastname: Oh
authors.forename: Jiadong
authors.initials: J
authors.lastname: Sun
authors.forename: Amir
authors.initials: A
authors.lastname: Nasrolahi Shirazi
authors.forename: Kerry L
authors.initials: KL
authors.lastname: LaPlante
authors.forename: David C
authors.initials: DC
authors.lastname: Rowley
authors.forename: Keykavous
authors.initials: K
authors.lastname: Parang
mesh_terms: D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D057846:Cell-Penetrating Peptides
keywords: antimicrobial peptide; cell-penetrating peptide; combination; drug delivery; methicillin-resistant Staphylococcus aureus