权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

MICA: Addressing the burgeoning problem of tuberculosis: Exploiting phenotypic hits to identify new protein targets for drug discovery

MICA：解决新兴的结核病问题：利用表型命中来识别药物发现的新蛋白质靶点

基本信息

批准号：
MR/R001154/1
负责人：
Gurdyal Besra
金额：
$ 115.59万
依托单位：
University of Birmingham
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FR001154%2F1
关键词：
MICA Addressing burgeoning problem tuberculosis

项目摘要

Mycobacterium tuberculosis, the microorganism causing tuberculosis (TB), is perhaps the single most important pathogen affecting mankind. Finding new antibiotics to cure TB is therefore one of the most pressing and exciting challenges in contemporary microbiology. Predominantly a disease of poverty, TB affects young adults in their productive years and hence also carries a large economic burden. Numbers published by the WHO are bleak: in 2015, approximately 9-10 million new cases of TB were reported and over 1 million people died from the disease. TB may be prevalent in the developing world but is also resurfacing in wealthy countries, with some 5,758 cases reported in 2015 in the UK alone. And yet, there is reason for cautious optimism. TB can be cured, albeit with a cocktail of drugs that need to be taken for at least six months. Moreover, new compounds, selected specifically for their ability to overcome the growing list of M. tuberculosis strains that are resistant to established drugs, are beginning to populate a small pipeline of potential future drugs. Indeed, in late 2012 and after a nearly 50-year hiatus, the FDA approved a new TB drug for clinical use. Still, the challenges of antibiotic discovery and development of drugs for treating TB remain formidable as M. tuberculosis is well shielded against most antibiotics by its unique cell-wall architecture. Such challenges are best met by combining expertise from the academic and pharmaceutical sectors, as this will ensure the development of new treatments is founded on a detailed knowledge of the biology of the bacterium. The principal aim of the proposed academic-industrial collaboration is to discover and validate new targets, which will provide the bedrock of future global TB drug-discovery activities. Using high-throughput screening of compound libraries, our industrial partners have identified a number of small molecules (so-called 'hits'), which kill M. tuberculosis. Working with our industrial partner, we have already amassed a considerable body of preliminary data. Combining traditional genetic and cutting-edge analytical tools, we have identified the cellular targets for some of these hits, some of which have been fed into the pipeline of activities that sees an initial hit developed into a drug. Significantly, in determining the mode of action for one of these new inhibitors we were also able to uncover novel features of lipid metabolism in mycobacteria. A number of very promising hits have now emerged from two new screening campaigns. These are primed for development and have been ranked by our industrial partners based on i) their potency and ii) key physicochemical properties, which predict their potential for successful drug development. These prioritised hits will be transferred to Birmingham and the Crick where we will use our expertise to identify the mycobacterial proteins that these molecules act upon and then elucidate how these compounds kill bacilli, i.e. their mode of action. From these studies we will discover novel fundamental biology of M. tuberculosis. We will also find out where this organism is particularly vulnerable, which will be vital for directing future TB drug-discovery activities. Drug discovery is highly multidisciplinary. The proposed collaboration and rich body of preliminary data present a compelling opportunity to unite basic and applied science and turn this into knowledge that can be used to treat a debilitating disease which represents one of the most pressing healthcare challenges for society in the 21st Century.

结核分枝杆菌是引起结核病的微生物，可能是影响人类的最重要的单一病原体。因此，寻找新的抗生素来治愈结核病是当代微生物学最紧迫和最令人兴奋的挑战之一。结核病主要是一种贫困疾病，影响处于生产年龄段的年轻人，因此也带来很大的经济负担。世界卫生组织公布的数字令人沮丧：2015年，约有900万至1000万新结核病病例报告，100多万人死于这种疾病。结核病可能在发展中国家流行，但也在富裕国家重新出现，仅在英国就报告了约5758例结核病病例。然而，我们有理由保持谨慎乐观。结核病是可以治愈的，尽管需要服用至少六个月的混合药物。此外，新化合物之所以被选中，是因为它们有能力克服越来越多对现有药物产生抗药性的结核分枝杆菌菌株，它们正开始在一小部分潜在的未来药物流水线中出现。事实上，在2012年底，在中断了近50年后，FDA批准了一种新的结核病药物用于临床。尽管如此，抗生素的发现和治疗结核病药物的开发仍然面临着艰巨的挑战，因为结核分枝杆菌独特的细胞壁结构很好地抵御了大多数抗生素的攻击。应对这些挑战的最佳方式是将学术和制药部门的专业知识结合起来，因为这将确保新治疗方法的开发建立在对细菌生物学的详细知识的基础上。拟议的学术-产业合作的主要目的是发现和验证新的靶点，这将为未来的全球结核病药物发现活动提供基础。通过对化合物文库的高通量筛选，我们的工业合作伙伴已经确定了一些小分子(所谓的HITS)，它们可以杀死结核分枝杆菌。与我们的工业伙伴合作，我们已经积累了相当多的初步数据。结合传统的遗传和尖端分析工具，我们已经确定了其中一些击中的细胞靶点，其中一些已经被输入到活动管道中，看到最初的击中发展成一种药物。值得注意的是，在确定其中一种新抑制剂的作用模式时，我们还能够发现分枝杆菌脂代谢的新特征。现在，两个新的放映活动已经产生了一些非常有希望的热门影片。这些药物已经为开发做好了准备，我们的工业合作伙伴根据i)它们的效力和ii)关键的物理化学特性对它们进行了排名，这些特性预测了它们成功药物开发的潜力。这些优先的打击将被转移到伯明翰和克里克，在那里我们将利用我们的专业知识来识别这些分子作用的分枝杆菌蛋白质，然后阐明这些化合物是如何杀死杆菌的，即它们的作用模式。通过这些研究，我们将发现结核分枝杆菌新的基础生物学。我们还将找出这种微生物特别脆弱的地方，这将对指导未来的结核病药物发现活动至关重要。药物发现是高度多学科的。拟议的合作和丰富的初步数据提供了一个令人信服的机会，可以将基础科学和应用科学结合起来，并将其转化为可用于治疗一种衰弱疾病的知识，这种疾病是21世纪社会面临的最紧迫的医疗挑战之一。