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

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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.