Comprehensive host cell-based drug discovery targeting innate immunity, virulence and essential functions of Mycobacterium tuberculosis

针对结核分枝杆菌的先天免疫、毒力和基本功能的综合宿主细胞药物发现

• 批准号: 326917100
• 负责人: Privatdozent Dr. Jan Rybniker, Ph.D.
• 金额: --
• 依托单位: Klinik für Innere Medizin I
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/326917100?language=en
• 关键词: Comprehensive; host; cell; based; drug

The emergence of multidrug resistant bacteria is a major public health concern with increased morbidity and mortality throughout the world. In addition to the search for novel antibiotics, alternative approaches, such as the development of anti-virulence drugs and adjunctive host directed therapies are necessary to fill the antibiotic gap that appeared in the past decade. We have developed a drug screening platform for the major human pathogen Mycobacterium tuberculosis (Mtb) that is capable of combining all three approaches in a single assay. Control of the current tuberculosis (TB) pandemic is threatened due to increasing multidrug resistance and the lack of novel substances active against this pathogen. Our comprehensive drug screening approach is based on virulence factor driven host cell-lysis. Proof of concept studies identified novel Mtb-specific antibiotics as well as anti-virulence drugs targeting the ESX-1 secretion system, a major mycobacterial virulence factor. We also found widely used corticosteroids to be highly protective for ESX-1 induced cytotoxicity. This is an intriguing finding since corticosteroids represent the only clinically approved adjunctive host-directed therapy for TB-treatment; however, their mechanism of action in active TB is unknown. Our assay provides the unique opportunity to study mechanisms of Mtb induced cytotoxicity and how corticosteroids interfere with these in favor of the host-cell. A second major aim of this proposal is the identification of novel antibiotics and anti-virulance drugs as well as drugs with corticosteroid-like behavior using the well-established cell survival assay and a library of more than 40,000 small molecules. Hit compounds will provide leads for new treatment options against multi-drug resistant Mtb. In addition, novel immunomodulatory agents can be identified that may find applications in other disease backgrounds such as autoimmune diseases or cancer. Our data will provide insight into pathogen-driven cytotoxicity and innate immunity counter measures with a strong focus on therapeutic interventions.

多重耐药细菌的出现是一个主要的公共卫生问题，在世界各地的发病率和死亡率增加。除了寻找新的抗生素外，替代方法，如开发抗毒力药物和抗宿主定向疗法，对于填补过去十年出现的抗生素空白是必要的。我们已经开发了一种针对人类主要病原体结核分枝杆菌（Mtb）的药物筛选平台，该平台能够在一次检测中结合所有三种方法。由于多药耐药性的增加和缺乏对这种病原体有活性的新物质，目前结核病（TB）大流行的控制受到威胁。我们的综合药物筛选方法是基于毒力因子驱动的宿主细胞裂解。概念验证研究确定了新的结核分枝杆菌特异性抗生素以及靶向ESX-1分泌系统（一种主要的分枝杆菌毒力因子）的抗毒力药物。我们还发现广泛使用的皮质类固醇对ESX-1诱导的细胞毒性具有高度保护作用。这是一个有趣的发现，因为皮质类固醇代表了唯一临床批准的结核病治疗的连续性宿主导向疗法;然而，它们在活动性结核病中的作用机制尚不清楚。我们的试验提供了独特的机会来研究结核分枝杆菌诱导的细胞毒性的机制，以及皮质类固醇如何干扰这些有利于宿主细胞。该提案的第二个主要目的是使用完善的细胞存活测定和超过40，000个小分子的文库鉴定新型抗生素和抗肿瘤药物以及具有皮质类固醇样行为的药物。Hit化合物将为针对多药耐药结核病的新治疗选择提供线索。此外，可以鉴定新的免疫调节剂，其可以在其他疾病背景如自身免疫性疾病或癌症中找到应用。我们的数据将提供对病原体驱动的细胞毒性和先天免疫应对措施的深入了解，并重点关注治疗干预措施。