导读：近日，中科院昆明动物研究所开展的眼镜王蛇毒OH-CATH30抗菌肽及衍生物的体内药效学评价获新进展，相关论文发表于《抗微生物剂与化疗》上。研究发现，眼镜王蛇毒OH-CATH30及衍生物在低于毒性剂量十分之一以下的安全剂量范围内，对于全身性和致死性耐药菌感染具有良好的治疗和保护作用。
近日，中科院昆明动物研究所开展的眼镜王蛇毒OH-CATH30抗菌肽及衍生物的体内药效学评价获新进展。相关研究成果已在线发表于美国著名药理学和药学杂志《抗微生物剂与化疗》上。该研究由博士生李盛安等人在研究员张云和李文辉带领下完成。
张云告诉《中国科学报》记者，感染是住院病人死亡的主要原因之一。据《新英格兰医学杂志》统计，仅在美国，每年败血症的患者为75万人，其中死亡22.5万。抗生素市场总额大约在300亿美元左右，但半个世纪以来，人们没有开发出真正意义上的新类型抗生素。随着传统抗生素的大量使用和滥用，在临床上出现了各种各样的耐药菌株，目前临床使用的抗生素对某些耐药菌已无疗效，成为人类健康的重大威胁。
抗菌肽是生物体内经诱导产生的一种具有生物活性的小分子多肽，这类活性多肽多数具有强碱性、热稳定性以及广谱抗菌等特点。在与致病菌变异竞争的过程中，自然界各种来源的抗菌肽成为人们研发新型抗感染药物的希望，但毒性和低下的体内药效成为限制大多数抗菌肽用于临床药物研发的瓶颈。
为攻克难题，李盛安等人在前期大量抗菌肽研究工作和相关发明专利“爬行动物cathelicidin抗菌肽及衍生物及其应用”基础上，建立了临床耐药菌感染动物模型。研究发现，在目前临床广泛使用的抗生素药物头孢哌酮钠无效的情况下，眼镜王蛇毒OH-CATH30及衍生物在低于毒性剂量十分之一以下的安全剂量范围内，对于全身性和致死性耐药菌感染具有良好的治疗和保护作用。
据悉，该研究获得国家重大新药创制专项、国家“973”计划项目和国家基金委—云南省联合基金项目的资助。
Efficacy of OH-CATH30 and its analogs against drug-resistant bacteria in vitro and in mouse models
Sheng-An Li, Wen-Hui Lee and Yun Zhang
Antimicrobial peptides (AMPs) have been considered as 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 analogs against drug-resistant bacteria in vitro and in vivo. The minimal inhibitory concentrations (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 dose (LD50) of OH-CATH30 and OH-CM6 in mice following intraperitoneal (i.p.) injection was 120 mg/kg 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.
文献链接：https://aac.asm.org/content/early/2012/04/02/AAC.06304-11
