Silver carbene complexes as treatment of CF lung disease

描述(申请人提供)：这些研究的长期目标是探索银卡宾复合体作为抗菌剂在肺部感染治疗中的效用，重点是治疗囊性纤维化(CF)肺的慢性感染。银-N-杂环卡宾化合物对目前测试的所有细菌都具有抗菌活性，包括CF肺部病原体铜绿假单胞菌和洋葱伯克霍尔德氏菌复合体(BCC)。银卡宾络合物是水溶性的，因此易于雾化给药。银化合物用于局部安全应用的历史悠久；然而，使用银化合物治疗肺部感染还没有被探索过。除了旨在确定银配合物对呼吸道上皮细胞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对主要的CF病原体铜绿假单胞菌以及不太常见的基底细胞癌生物体的治疗效果，特别是最近一次疫情的病原体杜氏杆菌。在BCC生物体中，对抗生素耐药性最强的是白色念珠菌。几乎对杜氏杆菌引起的肺部感染的发病机制知之甚少，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多发性巴氏杆菌感染的小鼠模型，并使用该模型以及更多已建立的铜绿假单胞菌肺部感染模型，来测试这些新开发的银基抗菌剂的体内特性。具体地说，我们的目标是1)合成作为候选抗菌剂的银卡宾化合物；2)确定物理性能最有希望的银卡宾化合物的抗菌性能和毒性特征，以及上皮细胞-银的毒性或解毒机制；3)建立慢性肺部感染耐药CF病原体的小鼠模型，并利用这些模型来确定领先的银卡宾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.