Drug Discovery from Slow Growing and Rare Microbial Species

从生长缓慢的稀有微生物物种中发现药物

基本信息

批准号：
8455539
负责人：
Amy Lynn Spoering
金额：
$ 99.97万
依托单位：
NOVOBIOTIC PHARMACEUTICALS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8455539
关键词：
Actinobacteria class Acute Animal Model Anti-Bacterial Agents Antibiotics Back Bacteria Biological Availability Biological Factors Blood Cell Separation Cells Chronic Clinical Research Collection Complex Cyclic Peptides Daptomycin Development Drug resistance Enterobacteriaceae Escherichia coli Evaluation Fermentation Frequencies Genus Mycobacterium Goals Individual Infection Lactamase Lead Libraries Linezolid Maximum Tolerated Dose Methods Mining Modeling Multi-Drug Resistance Mus Mycobacterium tuberculosis Peptide Hydrolases Pharmaceutical Preparations Phase Plasma Production Property Pseudomonas aeruginosa Public Health Resistance Resistance development Resources Running Safety Septicemia Soil Source Staphylococcus aureus Structure Testing Thigh structure Time Tuberculosis Validation Vancomycin resistant enterococcus Work Yeasts analytical method animal efficacy antimicrobial bactericide base combat cytotoxicity design drug discovery drug resistant bacteria genome sequencing in vivo innovative technologies liquid chromatography mass spectrometry member methicillin resistant Staphylococcus aureus microbial microorganism mouse model mutant mycobacterial novel novel therapeutics pathogen pre-clinical preclinical study public health relevance scale up screening soil sampling success

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this project is to discover novel antibiotics to combat important drug-resistant pathogens. We are running out of treatment options for pathogens such as S. aureus MRSA, vancomycin-resistant Enterococci (VRE), multidrug-resistant P. aeruginosa, A. baumannii, ESBL and New Delhi metallo-b- lactamase-producing Enterobacteriaceae, and M. tuberculosis. Only 3 novel antibiotics have been introduced in the past thirty years - linezolid, daptomycin, and fidaxomicin. Linezolid and fidaxomicin were discovered in the 60s, but did not appear sufficiently attractive at the time. With this pace of discovery, it is not surprising that resistance is on the rise. It is becoming increasingly apparent that the bottleneck in antibiotic discovery is the lack of good starting compounds. Not a single drug came out of HTS of synthetic compound libraries. Secondary metabolites produced by actinomycetes have been the main source of antibiotics, but this resource was over mined. At the same time, there is a potentially very large untapped source of natural products - previously uncultured bacteria that make up the vast majority of all bacterial species. Slow- growing species that require months to form colonies on a Petri dish are an important component of this majority. We reasoned that slow growers may actually represent dormant forms of bacteria, and will rapidly grow upon reinoculation. The majority of slow growers can indeed be rapidly cultured upon reinoculation, and many of the isolates represent previously unknown species and genera. In Phase I, we developed a method to simultaneously isolate and culture slow growers by placing individual cells in wells of a microtiter plate. Screening 5,000 of these isolates produced 3 new antimicrobial compounds, including Novo23 that acts specifically against M. tuberculosis. The target of Novo23 is the ClpC1 subunit of the essential mycobacterial ClpP protease. Novo23 has low cytotoxicity, favorable tolerability and blood levels in mice. We will examine efficacy of Novo23 in mouse models of tuberculosis. Further development of our three novel antibacterials are a major focus of Phase II. However, we recognize that only a small fraction of leads makes it to a drug. Thus, we will also undertake a large-scale discovery effort to identify additional antibacterials which will enter validation as they become available. Novel compounds will be examined for spectrum, potency, resistance development, stability, mechanism of action, and novelty of structure. Leads that emerge will be tested in mouse models of infection. The end result of Phase II will be three lead compounds showing efficacy in animal models. This will enable subsequent preclinical development towards an IND, clinical studies, and FDA approval of a new therapeutic. We believe this strategy - advancing leads while backing them with a discovery pipeline - greatly increases the chances for the project's success.

描述（由申请人提供）：该项目的总体目标是发现新颖的抗生素来对抗重要的耐药病原体。我们的病原体缺乏治疗选择，例如金黄色葡萄球菌MRSA，耐万古霉素的肠球菌（VRE），耐多药的铜绿假单胞菌，A。Baumannii，ESBL和New Delhi Metallo Metallo-B--甲状腺乳酸 - 乳酸 - 乳酸 - 乳糖酶生产肠to蛋白酶科和M. tuberosis。在过去的三十年中，仅引入了3种新型抗生素 - linezolid，daptomycin和fidaxomicin。在60年代发现了LineZolid和Fidaxomicin，但当时似乎没有足够的吸引力。以这种发现的速度，抵抗力正在上升并不奇怪。越来越明显的是，抗生素发现中的瓶颈缺乏良好的起始化合物。没有一种药物来自合成化合物库的HTS。放线菌产生的次生代谢产物一直是抗生素的主要来源，但是该资源过度挖掘了。同时，有一个可能非常大的未开发的天然产物来源 - 构成所有细菌物种中绝大多数的以前未培养的细菌。需要数月在培养皿上形成菌落的缓慢增长是这一重要组成部分。我们认为，缓慢的种植者实际上可能代表了休眠的细菌形式，并在重新联系时会迅速生长。大多数缓慢的种植者确实可以在重新联系后迅速培养，许多分离株代表以前未知的物种和属。在第一阶段，我们开发了一种通过将单个细胞放置在微量盘板的孔中，以同时隔离和培养慢速生长。筛选5,000种分离株产生了3种新的抗菌化合物，包括专门针对结核分枝杆菌的NOVO23。 NOVO23的靶标是基本分枝杆菌CLPP蛋白酶的CLPC1亚基。 NOVO23的细胞毒性低，有利的耐受性和小鼠的血液水平。我们将检查Novo23在肺结核小鼠模型中的功效。我们三种新型抗菌物的进一步发展是II期的主要重点。但是，我们认识到只有一小部分铅使它成为药物。因此，我们还将进行大规模发现的努力，以识别其他抗菌作用，这些抗菌将进入验证它们可用。新颖的化合物将检查频谱，效力，抗性发展，稳定性，作用机理和结构的新颖性。导致出现的铅将在小鼠感染模型中进行测试。第二阶段的最终结果将是三种铅化合物，显示动物模型的功效。这将使随后的临床前开发用于IND，临床研究和FDA的批准。我们认为，这种策略 - 推进潜在客户，同时通过发现管道来支持他们 - 大大增加了项目成功的机会。