Lead Compound Discovery from Engineered Analogs of Occidiofungin

项目摘要 八角菌素是一种环状非核糖体合成的亚微摩尔抗菌肽 对广谱真菌的杀菌活性。食用菌由葛兰素史克公司生产。 负细菌污染伯克霍尔德氏菌。从我们的结构表征研究来看， 球孢菌素具有独特的化学成分。我们的研究还包括 揭示了球孢菌素具有新的作用机制。食用菌是一种强效药物。 对氟康唑和卡泊芬净耐药白色念珠菌的抗真菌作用。金雀花素 通过诱导酵母细胞的凋亡来触发细胞死亡。地塞米松对人体的毒性最小 小鼠以2 mg/kg剂量进行28天的毒性研究。此外，球孢菌素被证明是 降低感染小鼠肾脏中光滑念珠菌的载量。所有这些研究都表明有必要 以促进这种新化合物的临床前开发。进一步发展的主要需要 对这种独特的抗真菌化合物的调查研究是对一种铅的鉴定 用于临床前试验的分子。这个应用程序的目标是筛选一个自然和 用于生物活性测试的半合成球孢菌素类似物。最好的化合物 属性将用于所需的临床前测试，这些测试是在我们的初始 与食品和药物管理局会面。这项工作对于进一步研究以下目标是必要的 开发抗真菌化合物作为一种新的治疗方法。

Project Summary Occidiofungin is a cyclic nonribosomally synthesized antifungal peptide with submicromolar fungicidal activity against a broad spectrum of fungi. Occidiofungin is produced by the Gram- negative bacterium Burkholderia contaminans. From our structural characterization studies, occidiofungin was determined to have a unique chemical composition. Our studies have also revealed that occidiofungin has a novel mechanism of action. Occidiofungin is a potent antifungal against fluconazole and caspofungin-resistant Candida albicans. Occidiofungin triggers cell death by inducing apoptosis in yeast cells. Occidiofungin has minimal toxicity in mice dosed with 2 mg/kg in a 28 day toxicity study. Furthermore, occidiofungin was shown to reduce Candida glabrata load in the kidneys of infected mice. All these studies point to the need to further the preclinical development of this novel compound. A major need for furthering investigational studies on this unique antifungal compound is the identification of a lead molecule for preclinical testing. The goal of this application is to screen a library of natural and semi-synthetic analogs of occidiofungin for bioactivity testing. The compound that has the best properties will be used in the required preclinical tests that are compulsory before our initial meeting with the FDA. This work is necessary for furthering additional studies aimed at developing the antifungal compound as a new therapeutic.