Abstract：
Modern medicine continues to struggle against antibiotic-resistant bacterial pathogens. Among the pathogens of critical concerns are the multidrug-resistant (MDR) Pseudomonas aeruginosa, Staphylococcus aureus, and Klebsiella pneumoniae. These pathogens are major causes of nosocomial infections among immunocompromised individuals, involving major organs such as lung, skin, spleen, kidney, liver, and bloodstream. Therefore, novel approaches are direly needed. Recently, we developed an amphiphilic dendrimer DDC18-8A exhibiting high antibacterial and antibiofilm efficacy in vitro. DDC18-8A is composed of a long hydrophobic alkyl chain and a small hydrophilic poly(amidoamine) dendron bearing amine terminals, exerting its antibacterial activity by attaching and inserting itself into bacterial membranes to trigger cell lysis. Here, we examined the pharmacokinetics and in vivo toxicity as well as the antibacterial efficacy of DDC18-8A in mouse models of human infectious diseases. Remarkably, DDC18-8A significantly reduced the bacterial burden in mouse models of acute pneumonia and bacteremia by P. aeruginosa, methicillin-resistant S. aureus (MRSA), and carbapenem-resistant K. pneumoniae and neutropenic soft tissue infection by P. aeruginosa and MRSA. Most importantly, DDC18-8A outperformed pathogen-specific antibiotics against all three pathogens by achieving a similar bacterial clearance at 10-fold lower therapeutic concentrations. In addition, it showed superior stability and biodistribution in vivo, with excellent safety profiles yet without any observable abnormalities in histopathological analysis of major organs, blood serum biochemistry, and hematology. Collectively, we provide strong evidence that DDC18-8A is a promising alternative to the currently prescribed antibiotics in addressing challenges associated with nosocomial infections by MDR pathogens.
摘要：
现代医学继续与抗生素抗性细菌病原体作斗争。在关键关注的病原体是多药耐药（MDR）铜绿假单胞菌，金黄色葡萄球菌,和肺炎克雷伯菌.这些病原体是免疫受损个体医院感染的主要原因，涉及肺等主要器官，皮肤,脾,脾肾,肝脏,和血液。因此,迫切需要新的方法。最近,我们开发了一种两亲性树枝状聚合物DDC18-8A，在体外具有高抗菌和抗生物膜功效。DDC18-8A由长的疏水烷基链和带有胺末端的小的亲水聚(酰胺基胺)树枝状体组成，通过将自身附着并插入细菌膜以触发细胞裂解来发挥其抗菌活性。这里,我们研究了DDC18-8A在人类传染病小鼠模型中的药代动力学和体内毒性以及抗菌功效。值得注意的是,DDC18-8A显着降低了铜绿假单胞菌急性肺炎和菌血症小鼠模型中的细菌负荷，耐甲氧西林金黄色葡萄球菌（MRSA），以及耐碳青霉烯类肺炎克雷伯菌和中性粒细胞减少性软组织感染铜绿假单胞菌和MRSA。最重要的是,DDC18-8A通过在低10倍的治疗浓度下实现相似的细菌清除而优于针对所有三种病原体的病原体特异性抗生素。此外,它在体内表现出优越的稳定性和生物分布，具有出色的安全性，但在主要器官的组织病理学分析中没有任何可观察到的异常，血清生物化学，和血液学。总的来说，我们提供了强有力的证据,证明DDC18-8A在解决与MDR病原体医院感染相关的挑战方面是目前处方抗生素的有希望的替代品.
