Isolating novel fungi for antibiotic discovery

分离新真菌以发现抗生素

• 批准号: 8288280
• 负责人: Losee Lucy Ling
• 金额: $ 99.93万
• 依托单位: NOVOBIOTIC PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288280
• 关键词: Acinetobacter; Actinobacteria class; Acute; Agar; Animal Model; Animal Testing; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Architecture; Biodiversity; Biological; Biological Assay; Biological Testing; Bioterrorism; Burkholderia; Cephalosporins; Clinical; Collection; Communicable Diseases; Community Hospitals; Development; Engineering; Enterobacter; Escherichia coli; Evaluation; Frequencies; Goals; Gram-Negative Bacteria; Growth; Human; Hyphae; In Situ; In Vitro; Infection; Klebsiella; Klebsiella pneumonia bacterium; Laboratories; Lactams; Lead; Lung; Maximum Tolerated Dose; Membrane; Methods; Molecular; Multi-Drug Resistance; Mus; New Agents; Organism; Pharmaceutical Preparations; Phase; Pneumonia; Probability; Property; Pseudomonas; Public Health; Resistance; Resistance development; Resources; Roentgen Rays; Running; Septicemia; Sequence Analysis; Serum; Soil; Solid; Solutions; Source; Staphylococcus aureus; Sterility; Structure; Technology; Testing; Toxic effect; United States; Validation; Vancomycin resistant enterococcus; Work; antimicrobial; antimicrobial drug; base; biodefense; cytotoxicity; drug development; drug discovery; fungus; genome sequencing; in vivo; meetings; methicillin resistant Staphylococcus aureus; microbial; microorganism; new technology; novel; pathogen; programs; public health relevance; research study; resistance mutation; resistant strain

DESCRIPTION (provided by applicant): The goal of this project is to discover and develop novel broad-spectrum antibiotics acting against critically important human pathogens. The unmet need is especially acute for Gram-negative pathogens, where we are rapidly running out of options for treating multidrug resistant species of Pseudomonas, Acinetobacter, Burkholderia, Klebsiella and Enterobacter. This is a challenging goal, since the last novel class of broad-spectrum antibiotics was discovered 40 years ago. Currently, there are no broad-spectrum leads in the global pipeline of drug discovery, according to the review of this important subject at the last ICAAC meeting. The main barrier to progress in antimicrobial drug discovery is the lack of sources for novel compounds. NovoBiotic has a proprietary technology capable of meeting this challenge. We are obtaining new antimicrobials from a previously inaccessible source - uncultured fungi. In Phase I, we developed a trap for specific capture and growth of uncultured fungi. Many antimicrobials, including ?-lactams and cephalosporins derive from culturable representatives of this group of microorganisms. The trap consists of two layers of sterile agar sandwiched between semi-permeable membranes that is inserted into soil. Fungi produce hyphae which enable them to penetrate into the trap through the pores in the membrane, into the upper layer of agar and form pure colonies. Many uncultured species that initially grow in situ are then capable of growing under standard laboratory conditions in vitro. The aims of Phase I were to assemble a collection of 200 fungi using the trap method, screen them for antimicrobial activity and dereplicate 25 of them. We achieved these milestones and discovered a novel broad- spectrum antimicrobial, Novo15, from an uncultured fungus only distantly related to known organisms. In Phase II we will validate the compounds discovered in Phase I in in vitro biological assays and animal models of S. aureus and K. pneumonia pulmonary infection. Also, we will isolate and screen an additional 250,000 fungal strains from the trap (Aim 1), validate potential leads using in vitro biological tests and determine the structure of promising compounds (Aim 2), and perform animal tests on 10 novel compounds (Aim 3). The end result of Phase II will be 2-3 validated, novel broad-spectrum antimicrobials. These will be developed into drugs in the next phase of the program. PUBLIC HEALTH RELEVANCE: There is increasing public health concern about the ability of currently available antibiotics to keep pace with evolving microbial resistance; naturally acquired in the case of community and hospital based infections, and potentially engineered in the case of bioterror agents. One solution to this problem is the development of new antibiotics. The purpose of this project is to use our new technology to identify new classes of antibiotics with broad-spectrum activity against both conventional and biodefense pathogens.

描述（由申请人提供）：该项目的目的是发现和开发针对至关重要的人类病原体作用的新型广谱抗生素。对于革兰氏阴性病原体，未满足的需求尤其急切，在那里，我们迅速无法选择用于治疗假单胞菌，阿科赛车，Burkholderia，Klebsiella和Enterobacter的多药耐药物种的选择。 这是一个具有挑战性的目标，因为在40年前发现了最后一类新颖的广谱抗生素类。目前，根据上次ICAAC会议的这一重要主题的评论，全球药物发现的渠道中没有广泛的潜在客户。抗菌药物发现进展的主要障碍是缺乏新颖化合物的来源。 Novobiotic具有一项能够应对这一挑战的专有技术。我们正在从以前无法访问的来源 - 未培养的真菌那里获得新的抗菌剂。在第一阶段，我们开发了一个陷阱，用于特定捕获和生长未培养的真菌。许多抗微生物，包括？ - lactams和头孢菌素，源自这组微生物的可培养代表。该陷阱由两层的无菌琼脂组成，这些无菌琼脂夹在插入土壤中的半渗透膜之间。真菌产生菌丝，使它们能够通过膜中的孔穿透陷阱，进入琼脂上层并形成纯菌落。然后，许多最初原位生长的未养殖物种能够在标准的实验室条件下体外生长。 第一阶段的目的是使用陷阱方法组装200个真菌，筛选它们以进行抗菌活性，并删除其中25个。我们实现了这些里程碑，并发现了一种新型的广泛抗菌抗菌剂Novo15，它是从一个与已知生物相关的未养殖真菌中发现的。在第二阶段，我们将验证在体外生物学测定中发现的化合物，以及金黄色葡萄球菌和肺炎肺炎的动物模型。此外，我们将从陷阱中隔离和筛选250,000个真菌菌株（AIM 1），使用体外生物学测试验证潜在的铅，并确定有希望的化合物的结构（AIM 2），并对10种新型化合物进行动物测试（AIM 3）。 II期的最终结果将为2-3个经过验证的新型广谱抗菌素。这些将在该计划的下一阶段发展为药物。 公共卫生相关性：人们对当前可用抗生素与不断发展的微生物抗性的能力的能力越来越关注；自然是在社区和基于医院的感染的情况下获得的，并有可能在Bioterror剂中进行设计。解决这个问题的一种解决方案是开发新的抗生素。该项目的目的是利用我们的新技术来识别针对常规和生物形式病原体具有广谱活性的新类抗生素。