PDF(Pubmed)
Abstract：
Polymyxins are the last line of defense against multidrug-resistant (MDR) Gram-negative bacterial infections. However, this last resort has been threatened by the emergence of superbugs carrying the mobile colistin resistance gene-1 (mcr-1). Given the high concentration of matrix metalloproteinase 3 (MMP-3) in bacterial pneumonia, limited plasma accumulation of colistin (CST) in the lung, and potential toxicity of ionic silver (Ag+), we designed a feasible clinical transformation platform, an MMP-3 high-performance lung-targeted bio-responsive delivery system, which we named \"CST&Ag@CNMS\". This system exhibited excellent lung-targeting ability (>80% in lungs), MMP-3 bio-responsive release property (95% release on demand), and synergistic bactericidal activity in vitro (2-4-fold minimum inhibitory concentration reduction). In the mcr-1+ CST-resistant murine pneumonia model, treatment with CST&Ag@CNMS improved survival rates (70% vs. 20%), reduced bacteria burden (2-3 log colony-forming unit [CFU]/g tissue), and considerably mitigated inflammatory response. In this study, CST&Ag@CNMS performed better than the combination of free CST and AgNO3. We also demonstrated the superior biosafety and biodegradability of CST&Ag@CNMS both in vitro and in vivo. These findings indicate the clinical translational potential of CST&Ag@CNMS for the treatment of lung infections caused by CST-resistant bacteria carrying mcr-1.
摘要：
多粘菌素是抵抗多药耐药（MDR）革兰氏阴性细菌感染的最后一道防线。然而,携带移动粘菌素抗性基因-1（mcr-1）的超级细菌的出现威胁到了最后的手段。考虑到细菌性肺炎中基质金属蛋白酶3（MMP-3）的高浓度，粘菌素（CST）在肺中的血浆积累有限，和离子银（Ag+）的潜在毒性，我们设计了一个可行的临床转化平台，MMP-3高性能肺靶向生物响应递送系统，我们命名为“CST&Ag@CNMS”。该系统表现出优异的肺靶向能力（>80％的肺部），MMP-3生物响应性释放特性（按需释放95％），和体外协同杀菌活性（最小抑制浓度降低2-4倍）。在mcr-1+CST耐药鼠肺炎模型中，CST&Ag@CNMS治疗提高了生存率（70%vs.20%),减少细菌负担（2-3对数菌落形成单位[CFU]/g组织），并显著减轻炎症反应。在这项研究中,CST和Ag@CNMS的表现优于游离CST和AgNO3的组合。我们还证明了CST＆Ag@CNMS在体外和体内的优异生物安全性和生物降解性。这些发现表明CST和Ag@CNMS用于治疗由携带mcr-1的CST抗性细菌引起的肺部感染的临床转化潜力。
