Using Fragment-based Drug Discovery (FBDD) to identify selective inhibitors against folate pathway enzymes from pathogenic microorganisms

传染病是人类死亡的主要原因之一，对最常见的抗菌剂产生抗药性加剧了这一问题。抗菌素耐药性是一个全球性问题，多项预测表明，到2050年，传染病将成为死亡的主要原因。因此，发现新的抗菌剂的研究成为包括英国在内的几个国家的优先事项。在这些微生物中，包括粪肠球菌、金黄色葡萄球菌、肺炎克雷伯菌、鲍曼不动杆菌、铜绿假单胞菌和肠杆菌在内的所谓ESKAPE类，以及包括结核分枝杆菌在内的分枝杆菌，已经受到了几个公共部门的高度重视。这些细菌对医疗保健有担忧，它们通常与医院感染有关，或者是难以治疗的，几乎没有抗菌药选择。除了细菌问题，由真菌金黄色念珠菌引起的疾病也令人震惊，因为它在医疗保健环境中爆发，对大多数抗真菌药物具有天生的抵抗力，以及在卫生和感染控制方法下的强烈韧性。金黄色念珠菌是一种新出现的病原体，于2009年首次报道，现已在全球传播。面对这一问题，我们希望将基于片段的药物发现策略应用于参与不同传染病病原体叶酸代谢的酶，包括结核分枝杆菌、鲍曼不动杆菌和金黄色葡萄球菌。利用结晶学、等温滴定热法(ITC)、差示扫描荧光法(DSF)和核磁共振(NMR)等多种生物物理技术的集成，结合计算技术和有机化学，我们有望根据先前识别和表征的针对这些病原体的二氢叶酸还原酶的分子(片段)，进化出一系列具有高亲和力和选择性的化合物。我们还预计，这些分子对参与叶酸新陈代谢的人类酶有不良影响。该项目涉及与剑桥大学的克里斯·阿贝尔教授小组的密切合作，他在有机化学合成策略方面给予了大力支持。

Infectious diseases are among the leading causes of death of humankind and the emergence of resistance to the most common antimicrobial is aggravating this problem. Resistance to antimicrobials is a global issue and several predictions indicate that infectious diseases will become the major cause of mortality by 2050. Thus, the research in the discovery of new antimicrobials became a priority in several countries, including UK. Among the microorganisms, the so-called "ESKAPE" group, which includes Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp., and mycobacteria species including M. tuberculosis have received considerable attention from several public sectors. These bacteria have a concern for healthcare, and they are generally associated with nosocomial infectious or are of difficult treatment with just few antimicrobial choices. In addition to the bacterial problem, diseases caused by the fungi Candida auris, an emerging pathogen firstly reported in 2009 and now spready globally, is also alarming because of its outbreaks in the healthcare setting, its innate resistance to most of antifungal drugs and its drastic resilience under hygiene and infection control methods. In face of this problem, we would like to apply the strategy of Fragment Based Drug Discovery to enzymes involved in the folate metabolism of different aetiological agents of infectious diseases, including M. tuberculosis, A. baumannni and C. auris. Using the integration of several biophysical techniques, including crystallography, isothermal titration calorimetry (ITC), differential scanning fluorimetry (DSF) and nuclear magnetic resonance (NMR) in combination with computational techniques and organic chemistry, we expect to evolve series of compounds with high affinity and selectivity based on previously identified and characterised molecules (fragments) that target the enzyme Dihydrofolate Reductase from these pathogens. We also expect that these molecules have a poor effect on the human enzymes involved in folate metabolism. This project involves an intensive collaboration with Prof. Chris Abell group from the University of Cambridge, who gives strong support on organic chemistry synthesis strategies.