Oh Donghoon, Sun Jiadong, Nasrolahi Shirazi Amir, LaPlante Kerry L, Rowley David C, Parang Keykavous
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island , Kingston, Rhode Island 02881, United States.
Mol Pharm. 2014 Oct 6;11(10):3528-36. doi: 10.1021/mp5003027. Epub 2014 Sep 4.
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.
多重耐药病原体已成为一个重大的公共卫生问题。迫切需要开发具有替代作用机制的新型抗生素，以治疗危及生命的细菌感染。抗菌肽是一类主要的抗菌剂，与细胞穿透肽（CPP）具有两亲性和阳离子结构特性。在此，合成了几种两亲性环状CPP及其类似物，并对多重耐药病原体表现出强大的抗菌活性。在所有肽中，环状肽[R4W4]（1）对耐甲氧西林金黄色葡萄球菌表现出最强大的抗菌活性[MRSA，最低抑菌浓度（MIC）为2.67μg/mL]。环状[R4W4]和线性对应物R4W4对铜绿假单胞菌的MIC值分别为42.8和21.7μg/mL。在真核细胞中，肽1表现出预期的细胞穿透特性，在三种不同的人类细胞系中，浓度为15μM（20.5μg/mL）时细胞活力>84%。24小时时间杀灭研究评估了[R4W4]与2倍MIC的四环素联合使用时，对MRSA（MIC = 0.5μg/mL）的杀菌活性为四环素MIC的4至8倍，对大肠杆菌（MIC = 2μg/mL）的杀菌活性为2至8倍MIC。这项研究表明，当两亲性环状CPP与四环素等抗生素联合使用时，与单独使用抗生素相比，它们对多重耐药病原体具有显著益处。
