Efficacy of OH-CATH30 and Its Analogs against Drug-Resistant Bacteria In Vitro and in Mouse Models
Efficacy of OH-CATH30 and Its Analogs against Drug-Resistant Bacteria In Vitro and in Mouse Models
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OH-CATH30 及其类似物在体外和小鼠模型中对抗耐药细菌的功效
DOI：
10.1128/aac.06304-11
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发表时间：
2012-06-01
影响因子：
4.9
通讯作者：
Zhang, Yun
中科院分区：
文献类型：
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作者：
Li, Sheng-An;Lee, Wen-Hui;Zhang, Yun
摘要抗微生物肽（AMP）已被认为是传统抗生素的替代品，用于耐药细菌感染。然而，它们对真核细胞的毒性较高，体内疗效较差，阻碍了它们的临床应用。OH-CATH 30是一种新的抗菌肽，具有较强的体外抗菌活性。本研究的目的是评价OH-CATH 30及其类似物OH-CM 6在体外和体内对耐药菌的有效性。OH-CATH 30和OH-CM 6对几种致病菌种的耐药临床分离株的MIC范围为1.56 - 12.5 μg/ml，包括大肠埃希菌、铜绿假单胞菌和耐甲氧西林金黄色葡萄球菌。在25%人血清存在下，OH-CATH 30和OH-CM 6的MIC略有改变。OH-CATH 30和OH-CM 6对E.大肠杆菌快速（60分钟内）通过破坏细菌细胞质膜。重要的是，腹膜内（i. p.）注射的剂量分别为120 mg/kg体重和100 mg/kg，并且在皮下（s.c.）注射此外，10 mg/kg OH-CATH 30或OH-CM 6显著降低了小鼠大腿感染模型中的细菌计数以及炎症反应，并在由耐药大肠杆菌诱导的菌血症模型中拯救了感染小鼠。杆菌综上所述，我们的研究结果表明，天然cathelicidin肽OH-CATH 30及其类似物在小鼠模型中表现出相对较低的毒性和有效的疗效，表明它们可能对耐药菌引起的全身感染具有治疗潜力。
ABSTRACT Antimicrobial peptides (AMPs) have been considered alternatives to conventional antibiotics for drug-resistant bacterial infections. However, their comparatively high toxicity toward eukaryotic cells and poor efficacy in vivo hamper their clinical application. OH-CATH30, a novel cathelicidin peptide deduced from the king cobra, possesses potent antibacterial activity in vitro. The objective of this study is to evaluate the efficacy of OH-CATH30 and its analog OH-CM6 against drug-resistant bacteria in vitro and in vivo. The MICs of OH-CATH30 and OH-CM6 ranged from 1.56 to 12.5 μg/ml against drug-resistant clinical isolates of several pathogenic species, including Escherichia coli, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus. The MICs of OH-CATH30 and OH-CM6 were slightly altered in the presence of 25% human serum. OH-CATH30 and OH-CM6 killed E. coli quickly (within 60 min) by disrupting the bacterial cytoplasmic membrane. Importantly, the 50% lethal doses (LD50) of OH-CATH30 and OH-CM6 in mice following intraperitoneal (i.p.) injection were 120 mg/kg of body weight and 100 mg/kg, respectively, and no death was observed at any dose up to 160 mg/kg following subcutaneous (s.c.) injection. Moreover, 10 mg/kg OH-CATH30 or OH-CM6 significantly decreased the bacterial counts as well as the inflammatory response in a mouse thigh infection model and rescued infected mice in a bacteremia model induced by drug-resistant E. coli. Taken together, our findings demonstrate that the natural cathelicidin peptide OH-CATH30 and its analogs exhibit relatively low toxicity and potent efficacy in mouse models, indicating that they may have therapeutic potential against the systemic infections caused by drug-resistant bacteria.