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

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，寻找治疗结核病的新抗生素是当代微生物学中最紧迫和令人兴奋的挑战之一。结核病主要是一种贫困疾病，影响到处于生产年龄的年轻人，因此也带来了巨大的经济负担。世卫组织公布的数字令人沮丧：2015年，约有900万至1000万新发结核病病例报告，100多万人死于该病。结核病可能在发展中国家很流行，但也在富裕国家重新出现，2015年仅英国就报告了5758例病例。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6个月的混合药物。此外，新化合物被专门挑选出来，因为它们有能力克服越来越多的对现有药物具有耐药性的结核分枝杆菌菌株，这些化合物正开始填充一个潜在的未来药物的小管道。事实上，在2012年底，在中断了近50年之后，FDA批准了一种新的结核病药物用于临床。尽管如此，发现抗生素和开发治疗结核病的药物的挑战仍然是艰巨的，因为结核分枝杆菌通过其独特的细胞壁结构很好地屏蔽了大多数抗生素。这些挑战最好通过结合学术和制药部门的专业知识来解决，因为这将确保新疗法的开发建立在对细菌生物学的详细了解的基础上。拟议的学术-工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杀死结核分枝杆菌的小分子（所谓的“hit”）。通过与我们的工业伙伴的合作，我们已经积累了大量的初步数据。结合传统的基因和尖端的分析工具，我们已经确定了其中一些攻击的细胞靶点，其中一些已经被输入到活动管道中，看到最初的攻击发展成药物。值得注意的是，在确定这些新抑制剂之一的作用模式时，我们也能够揭示分枝杆菌脂质代谢的新特征。在两场新的放映活动中，出现了一些非常有希望的热门影片。这些药物已经准备好进行开发，并由我们的工业合作伙伴根据i)它们的效力和ii)关键的物理化学性质进行排名，这些性质预测了它们成功开发药物的潜力。这些优先的目标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，然后阐明这些化合物如何杀死杆菌，即它们的作用模式。从这些研究中，我们将发现结核分枝杆菌新的基础生物学。我们还将发现这种有机体在哪里特别脆弱，这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体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性疾病的知识，这种疾病是21世纪社会面临的最紧迫的卫生保健挑战之一。

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.