Lead Compound Discovery from Engineered Analogs of Occidiofungin

项目摘要 Occidiofungin是一种环状非核糖体合成的抗真菌肽， 对广谱真菌具有杀真菌活性。Occidiofungin是由革兰氏- 阴性细菌污染伯克霍尔德氏菌。从我们的结构特征研究来看， 确定了occidiofungin具有独特的化学组成。我们的研究也 揭示了occidiofungin具有新的作用机制。Occidiofungin是一种有效的 抗真菌药对氟康唑和卡泊芬净耐药的白色念珠菌。洋杉菌素 通过诱导酵母细胞凋亡引发细胞死亡。Occidiofungin具有最小的毒性， 在28天毒性研究中以2 mg/kg剂量给药小鼠。此外，occidiofungin被证明 减少感染小鼠肾脏中的光滑念珠菌负荷。所有这些研究都表明， 以促进这种新型化合物的临床前开发。一个主要的需要是进一步 对这种独特的抗真菌化合物的调查研究是鉴定出一种 用于临床前测试的分子。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球菌素的半合成类似物。最好的化合物 这些特性将用于在我们的初始测试之前必须进行的临床前测试。 与FDA会面。这项工作对于进一步开展旨在 开发抗真菌化合物作为新的治疗剂。

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.