Antibacterial Activities of Amphiphilic Cyclic Cell-Penetrating Peptides against Multidrug-Resistant Pathogens

被引:62
作者
Oh, Donghoon [1 ]
Sun, Jiadong [1 ]
Shirazi, Amir Nasrolahi [1 ,2 ]
LaPlante, Kerry L. [3 ]
Rowley, David C. [1 ]
Parang, Keykavous [1 ,2 ]
机构
[1] Univ Rhode Isl, Coll Pharm, Dept Biomed & Pharmaceut Sci, Kingston, RI 02881 USA
[2] Chapman Univ, Sch Pharm, Irvine, CA 92866 USA
[3] Univ Rhode Isl, Dept Pharm Practice, Coll Pharm, Kingston, RI 02881 USA
基金
美国国家科学基金会; 美国国家卫生研究院;
关键词
antimicrobial peptide; cell-penetrating peptide; combination; drug delivery; methicillin-resistant Staphylococcus aureus; STAPHYLOCOCCUS-AUREUS; ANTIMICROBIAL PEPTIDES; UNITED-STATES; PSEUDOMONAS-AERUGINOSA; MOLECULAR TRANSPORTERS; DRUG-DELIVERY; DAPTOMYCIN; EPIDEMIOLOGY; INFECTIONS; MECHANISMS;
D O I
10.1021/mp5003027
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 mu g/mL]. Cyclic [R4W4] and the linear counterpart KIWI exhibited MEC values of 42.8 and 21.7 mu g/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 mu M (20.5 mu g/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 MESA (MIC = 0.5 mu g/mL) and 2-8 times the MIC against Escherichia coli (MIC = 2 mu g/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.
引用
收藏
页码:3528 / 3536
页数:9
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