Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, the Chinese Academy of Sciences, Kunming, Yunnan, China.
Antimicrob Agents Chemother. 2012 Jun;56(6):3309-17. doi: 10.1128/AAC.06304-11. Epub 2012 Apr 9.
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 (LD(50)) 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.
抗菌肽 (AMPs) 已被认为是治疗耐药性细菌感染的传统抗生素的替代品。然而，它们对真核细胞的相对较高毒性和体内疗效不佳限制了它们的临床应用。OH-CATH30 是一种从眼镜王蛇衍生的新型抗菌肽，具有体外强大的抗菌活性。本研究旨在评估 OH-CATH30 及其类似物 OH-CM6 对体外和体内耐药细菌的疗效。OH-CATH30 和 OH-CM6 的 MIC 范围为 1.56 至 12.5 μg/ml，针对几种致病性物种的耐药临床分离株，包括大肠杆菌、铜绿假单胞菌和耐甲氧西林金黄色葡萄球菌。在存在 25%人血清的情况下，OH-CATH30 和 OH-CM6 的 MIC 略有改变。OH-CATH30 和 OH-CM6 通过破坏细菌细胞质膜迅速杀死大肠杆菌（在 60 分钟内）。重要的是，OH-CATH30 和 OH-CM6 经腹腔（i.p.）注射后在小鼠中的 50%致死剂量（LD(50)）分别为 120 mg/kg 体重和 100 mg/kg 体重，经皮下（s.c.）注射后任何剂量均未观察到死亡，最高达 160 mg/kg。此外，10 mg/kg 的 OH-CATH30 或 OH-CM6 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，并在耐药大肠杆菌引起的菌血症模型中拯救了感染的小鼠。综上所述，我们的研究结果表明，天然抗菌肽 OH-CATH30 及其类似物在小鼠模型中具有相对较低的毒性和强大的疗效，表明它们可能具有治疗耐药细菌引起的全身感染的潜力。
