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型抗生素来对抗重要的耐药病原体。我们对金黄色葡萄球菌 MRSA、耐万古霉素肠球菌 (VRE)、多重耐药铜绿假单胞菌、鲍曼不动杆菌、ESBL 和新德里产金属 β-内酰胺酶肠杆菌科细菌和 M 等病原体的治疗选择已所剩无几。 . 结核病。在过去的三十年中，仅推出了 3 种新型抗生素：利奈唑胺、达托霉素和非达霉素。利奈唑胺和非达霉素在20世纪60年代被发现，但当时并没有表现出足够的吸引力。以这种发现速度，阻力不断增加也就不足为奇了。越来越明显的是，抗生素发现的瓶颈是缺乏良好的起始化合物。合成化合物库的 HTS 中没有产生任何药物。放线菌产生的次生代谢物一直是抗生素的主要来源，但这种资源被过度开采。与此同时，还有大量未开发的天然产物来源——以前未培养的细菌，它们构成了所有细菌种类的绝大多数。生长缓慢的物种是其中的重要组成部分，需要几个月的时间才能在培养皿上形成菌落。我们推断，缓慢生长的细菌实际上可能代表了休眠形式的细菌，并且在重新接种后会迅速生长。大多数慢速生长者确实可以在重新接种后快速培养，并且许多分离株代表了以前未知的物种和属。在第一阶段，我们开发了一种方法，通过将单个细胞放入微量滴定板的孔中来同时分离和培养生长缓慢的细胞。筛选了 5,000 个这些分离株，产生了 3 种新的抗菌化合物，其中包括专门针对结核分枝杆菌的 Novo23。 Novo23 的靶点是分枝杆菌必需的 ClpP 蛋白酶的 ClpC1 亚基。 Novo23 具有低细胞毒性、良好的耐受性和小鼠血药浓度。我们将检查 Novo23 在小鼠结核病模型中的功效。我们三种新型抗菌药物的进一步开发是第二阶段的主要重点。然而，我们认识到只有一小部分先导化合物可以制成药物。因此，我们还将进行大规模的发现工作，以确定其他抗菌药物，这些抗菌药物将作为他们变得可用。将检查新化合物的谱系、效力、耐药性发展、稳定性、作用机制和结构新颖性。出现的线索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先导化合物在动物模型中显示出功效。这将使新疗法的后续临床前开发、临床研究和 FDA 批准成为可能。我们相信这一策略——推进潜在客户，同时通过发现渠道支持他们——大大增加了项目成功的机会。