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

加速 CHNUK AMR 发现：建立中英联合培训和研究平台，实现基于高通量片段的抑制剂发现

• 批准号: MR/P007503/1
• 负责人: Christopher Dowson
• 金额: $ 91.43万
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP007503%2F1
• 关键词: Accelerate; CHNUK; AMR; discovery; Establishing

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.

抗菌药物耐药性（AMR）对中国和世界范围内的全球公共卫生构成日益严重的威胁。“ESKAPE”微生物中的多药耐药性--包括铜绿假单胞菌、金黄色葡萄球菌和大肠杆菌--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原因。这些微生物中的耐药性在革兰氏阴性菌中广泛存在，在中国引起特别关注，导致医院中碳青霉烯酶介导的耐药性的高患病率，包括最近出现的大肠埃希菌。大肠杆菌对最后一线药物粘菌素具有可传播的耐药性。显然，迫切需要新的抗菌药物来避免耐药性。在过去的20年里，只有两类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。主要受到青霉素早期成功的启发，开发了20种新的抗生素。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批准的困难和不可预测性，由此产生的低利润率以及随着耐药性水平持续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撤出对抗生素发现的投资。随之而来的该部门专门知识的损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AMR研究小组之间建立一个活动网络，来解决下一代研究人员缺乏专门的AMR培训的问题。我们将在先进的生物物理技术方面培养下一代研究人员，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，我们得到了行业的特殊支持，并收到了他们的支持信（为我们的5年英国合作SWON联盟科学计划提供了CHNUK基础科学的重要组成部分）。我们将安排联合SWON CHNUK科学顾问小组会议，以帮助重点关注基于片段的发现。中国和英国已承诺在结构生物学所需的同步加速器和相关光束线方面进行重大资本投资，此外，英国还承诺在基于片段的药物发现方面进行重大资本投资。自动化片段发现技术从哈威尔转移到上海（见支持信）将使在英国接受培训的中国研究人员能够将其可用的活动扩展到中国研究人员，进一步加速发现。

项目成果

To Push or To Pull? In a Post-COVID World, Supporting and Incentivizing Antimicrobial Drug Development Must Become a Governmental Priority.

• DOI: 10.1021/acsinfecdis.0c00681
• 发表时间: 2021-08-13
• 期刊: ACS infectious diseases
• 影响因子: 5.3
• 作者: Cama J;Leszczynski R;Tang PK;Khalid A;Lok V;Dowson CG;Ebata A
• 通讯作者: Ebata A

In vitro and in vivo activity of ML302F: a thioenolate inhibitor of VIM-subfamily metallo ß-lactamases

ML302F 的体外和体内活性：VIM 亚家族金属 γ-内酰胺酶的硫代烯醇盐抑制剂

• DOI: 10.1039/c5md00380f
• 发表时间: 2016
• 期刊: MedChemComm
• 作者: Betts J

The SGC beyond structural genomics: redefining the role of 3D structures by coupling genomic stratification with fragment-based discovery.

超越结构基因组学的 SGC：通过将基因组分层与基于片段的发现结合起来，重新定义 3D 结构的作用。

• DOI: 10.1042/ebc20170051
• 发表时间: 2017-11-08
• 期刊: Essays in biochemistry
• 影响因子: 6.4
• 作者: Bradley AR;Echalier A;Fairhead M;Strain-Damerell C;Brennan P;Bullock AN;Burgess-Brown NA;Carpenter EP;Gileadi O;Marsden BD;Lee WH;Yue W;Bountra C;von Delft F
• 通讯作者: von Delft F