Accelerate CHNUK AMR discovery: Establishing joint China/UK training and research platforms enabling highthroughput fragment based inhibitor discovery

抗微生物药物耐药性（AMR）是中国乃至世界范围内日益严重的公共卫生威胁。“ESKAPE”生物——包括铜绿假单胞菌、金黄色葡萄球菌和大肠杆菌——的多药耐药性加剧了这种情况，因为这些病原体是医院中许多危及生命的感染的罪魁祸首。这些生物的耐药性在中国特别关注的革兰氏阴性菌中广泛存在，导致医院碳青霉烯酶介导的耐药性高发，包括最近在大肠杆菌中出现的对最后一线药物粘菌素的传染性耐药性。显然，我们迫切需要能够避免耐药性的新型抗菌药物。在过去的20年里，只有两种新的抗生素被开发出来，这与抗生素发现的“黄金时代”相比是不利的。主要受青霉素早期成功的启发，开发了20种新型抗生素。除了抗菌药物发现的挑战和复杂性之外，阻碍新抗菌药物开发的因素还包括获得监管部门批准的难度和不可预测性，由此产生的低利润率以及随着耐药性水平不断上升而对使用的监管限制。这些因素导致制药和生物技术行业大幅退出抗生素研发投资。随之而来的该领域专业知识的流失只会加剧这种威胁。因此，迫切需要在培训和发现方面进行大量投资，以克服新抗菌药物的严重缺乏。我们计划通过在英国和中国优秀的、资金充足的抗微生物药物耐药性研究小组之间建立一个活动网络，解决下一代研究人员缺乏专业抗微生物药物耐药性培训的问题。我们将在先进的生物物理技术方面培养一批下一代研究人员，以加速发现新的化学抑制剂。这些化合物将被证明是探索生物学基本方面的宝贵工具，并成为开发新的抗菌发现计划的化学起点。为了实现这一目标，我们得到了工业界的大力支持，并获得了他们的支持函（为我们的5年英国合作SWON联盟科学计划提供了重要的基础科学组成部分）。我们将安排swn - CHNUK联合科学顾问小组会议，以帮助确定基于碎片的发现的优先事项。中英两国已承诺对结构生物学所需的同步加速器和相关束流线进行重大资本投资，此外在英国还将投资于基于片段的药物发现。将自动片段发现技术从哈维尔转移到上海（见支持函），将使在英国接受培训的中国研究人员能够将他们可用的活动扩展到中国研究人员，这是该计划的一部分，进一步加速发现。

Antimicrobial drug resistance (AMR) is a growing threat to global public health in China and worldwide. Multidrug resistance in 'ESKAPE' organisms - which includes Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli, exacerbates this as these pathogens are responsible for many life- threatening infections in hospitals. Resistance amongst these organisms is widespread in Gram-negative bacteria of particular concern in China causing a high prevalence of carbapenemase-mediated resistance in hospitals, including the recent emergence in E. coli of transmissible resistance to the last line drug, colistin. There is a clear and urgent need for new classes of antibacterials that sidestep resistance. Only two new classes of antibiotics have been developed in the last 20 years this compares unfavourably to the 'golden era' of antibiotic discovery, where. inspired primarily by the early successes of penicillins, 20 new antibiotic classes were developed. In addition to the challenges and complexities of antibacterial drug discovery, contributing factors halting the development of new antibacterials include the difficulty and indeed unpredictability of gaining regulatory approval, the resulting low profit margins and the regulatory restrictions on use as resistance levels continue to rise. These factors have seen the pharmaceutical and biotechnology industry substantially withdraw from investing in antibiotic discovery. The accompanying loss of expertise in the sector has only compounded the threat. Thus there is a pressing requirement for significant investment in training and discovery to overcome the woeful lack of new antibacterials.We plan to tackle the lack of specialised AMR training for the next generation of researchers by building a network of activity between outstanding, well funded, AMR research groups in the Uk and China. We will train a cohort of the next generation of researchers in advanced biophysical techniques to accelerate the discovery of new chemical inhibitors. These compounds will prove invaluable tools to probe fundamental aspects of biology and become the chemical start points for the development new antibacterial discovery programs. To achieve this we have exceptional support from industry and have included letters of support from them (for our 5yr UK collaborative SWON alliance science program which provides an important component of the underpinning science for CHNUK). We will arrange joint SWON CHNUK scientific advisory panel meetings to help focus priorities for fragment based discovery.China and the UK have committed major capital investment in synchrotrons and associated beam lines required for structural biology, and additionally in the UK for fragment based drug discovery. Transfer of automated fragment discovery technology from Harwell to Shanghai (see letters of support) will enable China researchers trained in the UK as part of this program to extend activities available to them to China researchers, further accelerating discovery.