权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Optimization of the Production and Isolation of the Novel Antifungal Occidiofungin

新型抗真菌药物 Occidiofungin 的生产和分离优化

基本信息

批准号：
9242586
负责人：
James Leif Smith
金额：
$ 23.42万
依托单位：
SANO CHEMICALS, INC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9242586
关键词：
Address Anabolism Antifungal Agents Apoptosis Bacteria Biological Biomedical Engineering Burkholderia Candida albicans resistance Candida glabrata Carbon Caspofungin Cell Count Cell Death Cells Chemicals Clinical Culture Media Data Development Disease Dose Escherichia coli Fermentation Fluconazole Gene Cluster Genes Genetic Genomics Goals Gram-Negative Bacteria Growth Human Industrial fungicide Infection Investigation Investigational New Drug Application Kidney Knowledge Life Liquid substance Methods Molecular Mus Mutagenesis Mycoses Names Natural Products Nitrogen Oxygen Peptides Periodicity Poaceae Predisposition Production Regulator Genes Regulatory Element Research Sodium Chloride Soil Source Structure-Activity Relationship System Techniques Temperature Therapeutic Time Toxic effect Work Yeasts base distilled alcoholic beverage efficacy study experience experimental study fungus genetic manipulation glycolipopeptide improved mutant novel novel therapeutics preclinical development preclinical study public health relevance

项目摘要

DESCRIPTION (provided by applicant): 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 at doses exceeding 10 mg/kg. 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. The major impediment to furthering investigational studies on this unique antifungal compound is the poor yield from culture liquor. The goal of this application is to enhance the yield and purity of occidiofungin following fermentation. Three approaches will be explored to increase the yield of the antifungal compound. First, media components will be screened to determine their effect on the production levels of the antifungal compound. Second, a molecular based approach will be used to determine whether an increase in production of occidiofungin is possible through genetic manipulation of B. contaminans. Our third approach is to develop a heterologous expression system. The last component of the application is to determine the most effective means of extracting and purifying the antifungal compound from the fermentation liquor. These studies will enable exploratory structure-activity relationship (SAR) studies on occidiofungin. This work is necessary for furthering additional studies aimed at developing the antifungal compound as a new therapeutic.

描述（由申请人提供）：Occidiofungin是一种环状非核糖体合成的抗真菌肽，对广谱真菌具有亚微摩尔杀真菌活性。Occidiofungin由革兰氏阴性细菌污染伯克霍尔德氏菌产生。从我们的结构表征研究中，确定occidiofungin具有独特的化学组成。我们的研究还表明，occidiofungin有一个新的作用机制。Occidiofungin是一种有效的抗真菌剂，可对抗氟康唑和卡泊芬净耐药的白色念珠菌。Occidiofungin通过诱导酵母细胞凋亡引发细胞死亡。在超过10 mg/kg的剂量下，Occidiofungin在小鼠中具有最小的毒性。此外，occidiofungin被证明可以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需要进一步开发这种新型化合物的临床前研究。对这种独特的抗真菌化合物进行进一步调查研究的主要障碍是培养液的产量低。本申请的目的是提高发酵后的球孢子菌素的产率和纯度。将探索三种方法来提高抗真菌化合物的产率。首先，将筛选培养基组分以确定其对抗真菌化合物的生产水平的影响。第二，将使用基于分子的方法来确定是否可能通过B的遗传操作来增加球孢子菌素的产量。污染物我们的第三种方法是开发异源表达系统。本申请的最后一个组成部分是确定从发酵液中提取和纯化抗真菌化合物的最有效方法。这些研究将使对occidiofungin的探索性构效关系（SAR）研究成为可能。这项工作是必要的进一步额外的研究，旨在开发抗真菌化合物作为一种新的治疗。