中国科学院昆明动物研究所机构知识库

医院感染或医院获得性感染是住院治疗中最常见的并发症之一，并且给发展中国家和发达国家的医疗保健事业造成了巨大的困境，其导致发病率和死亡率的增加、住院时间的延长，治疗范围的扩大，同时产生了巨大的经济负担。在过去的几十年中，医院病原体对常规抗生素存在严重的耐药性，这阻碍了对病原体感染的治疗，如尿路感染，导管相关血流感染，呼吸机相关性肺炎以及免疫功能低下患者的术后伤口感染。医院病原体中多重耐药性的增加和传播，以及开发和批准新抗生素所需的巨大费用和漫长周期，这些造成的全球医疗灾难加剧了对替代疗法的需求。抗菌肽（Antimicrobial peptides, AMPs）由于具有广泛的作用机制,不易产生抗药性及能够迅速对病原体产生作用等特性，被认为是解决上述威胁的最理想方案。抗菌肽存在于所有生物体中，在免疫反应中发挥着不可或缺的作用，能够作为抵抗病原体入侵的第一道防线。人们可通过对天然抗菌肽进行设计改造以进行针对多重耐药性病原体进行高效治疗，其中一些多肽类药物已进入临床试验的不同阶段，并且一些已经被美国食品和药物管理局（FDA）批准用于商业目的。在本文的研究中，我们在早期发现的天然抗菌肽Cathelicidin的基础上设计合成了仅含有17个氨基酸残基的多肽ZY4，ZY4对包括机会性铜绿假单胞菌和其他医院病原菌如鲍曼不动杆菌，大肠杆菌和金黄色葡萄球菌在内的几种革兰氏阴性和革兰氏阳性细菌均表现出广谱活性且强的抗菌作用；在脓毒性休克小鼠模型中ZY4能够抑制体内病原体的植入及向靶器官的传播，并抑制细胞因子的释放，而在铜绿假单胞菌诱导的肺病小鼠模型中ZY4能够通过抑制免疫细胞的浸润和促炎细胞因子的分泌来缓解肺部炎症；在体外实验中，ZY4还表现出抗生物膜活性，在血浆中具有强稳定性及对哺乳动物细胞的低毒性。此外，通过脱脂乳琼脂测定，SDS-PAGE及酶谱分析等实验，发现ZY4在铜绿假单胞菌菌株中能够上调蛋白水解活性但ZY4没有显著降解；同时，将病原体长期暴露于ZY4以选择性诱导其对ZY4的抗性，以抗生素Colistin作为对照，病原体未观察到对ZY4的显著的选择抗性，而抗生素Colistin通常被作为治疗多重耐药性病原体的最后手段。总之，上述结果表明ZY4作为多重耐药病原体相关医院感染的理想治疗药物具有广阔的临床应用前景。

Nosocomial infections or hospital-acquired infections are one of the most common complications of hospitalization and pose a huge predicament to global healthcare both in developing and developed countries resulting in increased morbidity and mortality, prolonged hospital stay, extensive treatment associated with a huge economic burden. Over the past decades, treatment of nosocomial pathogen infections such as urinary tract infections, catheter-associated bloodstream infections, ventilator-associated pneumonia, and post-surgical wound infections in immunocompromised patients has been impeded by the recalcitrance of nosocomial pathogens to conventional antibiotics. The global healthcare cataclysm as a result of the upsurge and dissemination of multidrug resistance among nosocomial pathogens together with the huge expense and lengthy time needed to develop and approve new antibiotics has intensified the demand for alternative therapies. Antimicrobial peptides (AMPs) are regarded as the most ideal solution to this menace, mainly due to their broad mechanism of action, low proclivity to actuate resistance and swift action on pathogens. Antimicrobials peptides exist naturally in all living organisms serving an integral role in immune responses acting as the first line of defense against invading pathogens. Natural AMPS have inspired the design of synthesis of highly effective therapeutic agents against multi-drug resistant pathogens most of which are in various stages of clinical trials and some already approved for use and commercial purposes by the Foods and Drugs Administration (FDA). In this study, we present a synthesized 17- amino acid residue polypeptide ZY4 designed from Cathelicidin BF-15. ZY4 exhibited broad-spectrum activity and strong antibacterial properties against several bacteria strains both gram-negative and gram-positive including the opportunistic Pseudomonas aeruginosa and other nosocomial pathogens such as Acinetobacter baumannii, Escherichia coli and Staphylococcus aureus. ZY4 suppressed in-vivo pathogen colonization and dissemination to target organs, inhibited cytokine release in mice models of septic shock. Alleviated lung inflammation by inhibiting the infiltration of immune cells and secretion of pro-inflammatory cytokines in P. aeruginosa induced lung disease mice models. ZY4 also exhibited in-vitro anti-biofilm activity, strong stability in plasma, and low toxicity to mammalian cells. Moreover, ZY4 upregulated proteolytic activity in P. aeruginosa strains without significant degradation of ZY4 as analyzed by Skim-milk agar assay, SDS-PAGE and Zymographic analysis. Also, upon Selective induction of resistance to ZY4 through long-term exposure of pathogens to this peptide, we did not observe a significant selection of resistance to ZY4 as compared to Colistin (Control) an antibiotic used as a last resort for treating multi-drug resistance pathogens. Taken collectively, these results suggest the potential of ZY4 as an ideal therapeutic agent for multi-drug resistant pathogen-related nosocomial infections.