Silver carbene complexes as treatment of CF lung disease

这些研究的长期目标是探索银卡宾配合物作为抗菌剂的效用 治疗肺部感染的药物，重点是治疗慢性感染， 囊性纤维化（CF）肺。银N-杂环卡宾配合物对所有 迄今为止检测的细菌菌种包括CF肺病原体铜绿假单胞菌和伯克霍尔德菌 洋葱复合体（BCC）生物。所述银卡宾络合物是水溶性的，并且因此适合于 雾化用于药物递送。银络合物具有长期安全用于局部应用的历史， 然而还没有探索使用银化合物治疗肺部感染。除了in 体外和体内毒性研究，旨在确定银络合物对呼吸系统的影响 上皮，我们将确定这些化合物用于治疗原发性CF病原体P的功效。 铜绿假单胞菌，以及不太常见的Bcc生物，特别是B。dolosa，一种 最近的流行病。B。在BCC生物体中，dolosa菌株是最具抗生素抗性的。几乎 对于由B引起的肺部感染的发病机理还一无所知。疼痛，没有有效的治疗方法 目前，这些患者。我们的目的是表征一种新的小鼠模型8。多洛萨感染和 使用该模型以及更成熟的铜绿假单胞菌肺部感染模型来测试体内 这些新开发的基于银的抗菌剂的性能。具体来说，我们的目标是1）合成 银卡宾络合物作为候选抗微生物剂; 2）测定抗微生物性质， 具有最有希望的物理性质的银卡宾化合物的毒性概况，以及 上皮细胞银毒性或解毒的机制;和3）开发慢性银中毒的小鼠模型。 肺部感染的耐药CF病原体，并使用这些模型来确定体内疗效 用于治疗肺部感染的主要银卡宾化合物。

The long-term goal of these studies is to explore the utility of silver carbene complexes as antimicrobial agents in the treatment of pulmonary infections with emphasis on treatment of the chronic infections of the cystic fibrosis (CF) lung. Silver N-heterocyclic carbene complexes have antimicrobial activity against all bacterial species tested to date including the CF lung pathogens Pseudomonas aeruginosa and Burkholderia cepacia complex (Bcc) organisms. The silver carbene complexes are water soluble, and hence amenable to nebulization for drug delivery. Silver complexes have a long history of safe use for topical applications, however, the use of silver compounds to treat pulmonary infections has not been explored. In addition to in vitro and in vivo toxicity studies aimed at determining the effects of silver complexes on the respiratory epithelium, we will establish the efficacy of these compounds for treatment of the primary CF pathogen P. aeruginosa, as well as the less common Bcc organisms, particularly B. dolosa, the causative agent of a recent epidemic. The B. dolosa strains are the most antibiotic resistant among the Bcc organisms. Virtually nothing is known about the pathogenesis of the lung infections caused by B. dolosa, and no effective therapy currently exists for these patients. We aim to characterize a novel murine model of 8. dolosa infection and use this model, as well as more established models of P. aeruginosa lung infections, to test the in vivo properties of these newly developed silver-based antimicrobial agents. Specifically, we aim to 1) synthesize silver carbene complexes as candidate antimicrobial agents; 2) determine the antimicrobial properties and toxicity profiles of the silver carbene compounds with the most promising physical properties, as well as the mechanisms of epithelial cell-silver toxicity or detoxification; and 3) develop murine models of chronic pulmonary infection with resistant CF pathogens and use these models to determine the in vivo efficacy of the leading silver carbene compounds for treatment of pulmonary infections.