Discovery of novel antibacterials from a mushroom natural product library

描述(申请人提供)：在重要的医院和社区获得的细菌病原体中，抗生素耐药性的流行急剧增加，对我们有效治疗传染病的能力构成了严重威胁。这一日益严重的问题要求开发不受现有耐药机制制约的新型抗菌剂。然而，最近在大型合成化合物库中寻找新的抗菌靶点和筛选靶标特异性抑制剂的努力基本上没有成功。由于现有的大多数抗生素都来自天然来源，因此人们对筛选独特的天然产品来源以寻找新的抗菌化合物重新产生了兴趣。为了满足对新型抗生素的需求，我们将从担子菌和子囊菌(蘑菇)的子实体提取物中鉴定和纯化抗菌化合物。这是一种独特的天然产物来源，没有经过系统的抗菌化合物筛选。LifePharms已经开发了一套广泛的近200,000种来自26,000多种独特真菌的预馏分天然产品提取物。在与MicroBiotix，Inc.的合作下，对该文库的一小部分进行了抗菌活性筛选。初步筛选出三种真菌对金黄色葡萄球菌具有抗菌活性的部分。这些组分的活性已经得到部分纯化，初步的抗菌活性测试表明，它们对一组抗生素耐药的革兰氏阳性病原体具有效力。我们的战略是进一步纯化和表征这些活性化合物的抗菌活性和化学新颖性，并继续筛选广泛的LifePharms新药文库。我们的目标是确定从蘑菇提取物中提取的具有强大抗菌活性的新型天然产品，并将其开发为治疗耐药生物的新型抗生素。在第一阶段，我们将提纯在初步筛选中确定的抗菌化合物，确定它们的结构，并在一系列旨在测量抗菌活性、细胞毒性和作用机制的测试中对它们进行评估。为了为这些分析提供更多的化合物，我们将筛选LifePharms抗菌化合物提取物集合的剩余部分。具有独特结构并满足特定效力、选择性和作用机制标准的纯化化合物将在第二阶段进一步开发与公共卫生相关：重要的医院和社区获得性细菌病原体中抗生素耐药性的流行急剧增加，对我们有效治疗传染病的能力构成严重威胁。，我们将从担子菌和子囊菌(蘑菇)子实体提取液中鉴定和纯化抗菌化合物。

DESCRIPTION (provided by applicant): The dramatic increase in the prevalence of antibiotic resistance among important hospital- and community-acquired bacterial pathogens poses a serious threat to our ability to effectively treat infectious diseases. This growing problem necessitates the development of novel antibacterial agents that are not subject to existing mechanisms of resistance. However, recent efforts to identify novel antibacterial targets and screen for target-specific inhibitors in large synthetic compound libraries have been largely unsuccessful. Because the majority of existing antibiotics are derived from natural sources, there is a renewed interest in screening unique sources of natural products for novel antibacterial compounds. To address the need for novel antibiotics, we will identify and purify antibacterial compounds from extracts derived from the fruiting bodies of basidiomycetes and ascomycetes (mushrooms). This represents a unique source of natural products has not been systematically screened for antibacterial compounds. LifePharms has developed an extensive collection of nearly 200,000 prefractionated natural product extracts derived from over 26,000 unique fungal species. In collaboration with Microbiotix, Inc. a small portion of the library has been screened for antibacterial activity. The preliminary screens indentified fractions from three fungal species with antibacterial activity against Staphylococcus aureus. The activities in these fractions have been partially purified, and preliminary antibacterial activity assays have demonstrated potency against a panel antibiotic-resistant Gram-positive pathogens. Our strategy is to further purify and characterize these active compounds for antibacterial activity and chemical novelty, and to continue screening the extensive LifePharms library for novel antibiotics. Our goal is to identify novel natural products derived from mushroom extracts with potent antibacterial activity, and to develop them into novel antibiotics to treat resistant organisms. In Phase I, we will purify the antibacterial compounds identified in preliminary screens, determine their structures, and evaluate them in a panel of assays designed to measure antibacterial activity, cytotoxicity, and mechanism of action. In order to provide additional compounds for these analyses, we will screen the remainder of the LifePharms collection of extracts for antibacterial compounds. Purified compounds that have a unique structure and meet the specified criteria for potency, selectivity, and mechanism of action will be developed further in Phase II PUBLIC HEALTH RELEVANCE: The dramatic increase in the prevalence of antibiotic resistance among important hospital- and community-acquired bacterial pathogens poses a serious threat to our ability to effectively treat infectious diseases. , We will identify and purify antibacterial compounds from extracts derived from the fruiting bodies of basidiomycetes and ascomycetes (mushrooms).