Silver carbene complexes as treatment of CF lung disease

描述（由申请方提供）：这些研究的长期目标是探索银卡宾络合物作为抗微生物剂在肺部感染治疗中的效用，重点是囊性纤维化（CF）肺部慢性感染的治疗。银N-杂环卡宾络合物对迄今为止测试的所有细菌物种具有抗微生物活性，包括CF肺病原体铜绿假单胞菌和洋葱伯克霍尔德氏菌复合体（Bcc）生物体。银碳烯络合物是水溶性的，因此适合于雾化用于药物递送。银络合物在局部应用中具有长期的安全使用历史;然而，尚未探索使用银化合物治疗肺部感染。除了旨在确定银络合物对呼吸道上皮影响的体外和体内毒性研究外，我们还将确定这些化合物治疗主要CF病原体铜绿假单胞菌以及不太常见的Bcc微生物（特别是B）的疗效。dolosa，最近流行病的病原体。B。在BCC生物体中，dolosa菌株是最具抗生素抗性的。事实上，对于由B引起的肺部感染的发病机理还一无所知。疼痛，目前对这些患者没有有效的治疗方法。我们的目的是表征一种新的小鼠模型的B。dolosa感染，并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这些新开发的基于银的抗微生物剂的体内性质。具体而言，我们的目标是：1）合成作为候选抗菌剂的银卡宾配合物; 2）确定具有最有希望的物理性质的银卡宾化合物的抗菌性能和毒性特征，以及上皮细胞-银毒性或解毒机制;和3）的方法开发具有耐药性CF病原体的慢性肺部感染的鼠模型，并使用这些模型来确定主要的银卡宾化合物用于治疗肺部感染。

DESCRIPTION (provided by applicant): 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 B. 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.