Silver carbene complexes as treatment of CF lung disease

描述（由申请人提供）：这些研究的长期目标是探索卡宾银配合物作为抗菌药物在肺部感染治疗中的应用，重点是治疗囊性纤维化（CF）肺的慢性感染。银n -杂环碳络合物对迄今为止测试的所有细菌物种都有抗菌活性，包括CF肺部病原体铜绿假单胞菌和洋葱伯克霍尔德菌复合体（Bcc）生物。银卡宾配合物是水溶性的，因此适于雾化给药。银配合物在局部应用方面有着悠久的安全使用历史；然而，使用银化合物治疗肺部感染尚未进行探索。除了旨在确定银复合物对呼吸上皮的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原发性CF病原体铜绿假单胞菌以及不太常见的Bcc生物体，特别是最近流行的病原体B. dolosa的功效。B. dolosa菌株是Bcc生物中最耐抗生素的菌株。实际上，我们对螺旋藻引起的肺部感染的发病机制一无所知，目前也没有针对这些患者的有效治疗方法。我们的目标是描述一种新的小鼠B. dolosa感染模型，并使用该模型以及更成熟的P. aeruginosa肺部感染模型来测试这些新开发的银基抗菌药物的体内特性。具体来说，我们的目标是1)合成银卡宾配合物作为候选抗菌药物；2)确定物理性质最有前途的银碳化合物的抗菌特性和毒性特征，以及上皮细胞银毒性或解毒的机制；3)建立具有耐药CF病原体的慢性肺部感染小鼠模型，并利用这些模型确定主要卡宾银化合物治疗肺部感染的体内疗效。

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.