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

Lead Research Organisation: University of Warwick
Department Name: School of Life Sciences

Abstract

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.

Technical Summary

The synchrotrons at Harwell (UK) and Shanghai (China) and the Drug Discovery unit at Dundee are powerful technology hubs. In particular Diamond Light Source is developing the first synchrotron beamline with an integrated high-throughput fragment based lead discovery (FBLD) platform and Dundee has established expertise in medicinal chemistry and drug discovery. We plan to integrate these hubs with AMR centres of excellence in China and the UK, deliver state of the art training to these researchers (and the wider AMR community) and exploit FBLD capabilities to identify novel chemical probes. These new chemical probes, alongside high throughput structural biology and mechanistic insight, will all importantly, help validate a range of novel AMR targets and provide the structural insight to build new effective inhibitors for these and the panel of well validated targets in cell wall and protein biosynthesis. Specialist workshops in China and the UK will deliver training and outreach to the wider community. To optimise and develop workflows at the interfaces between target production, fragment screening and medicinal chemistry and aid high-throughput characterization of novel targets two posts covering computational chemistry and structural biology are proposed. We will hold workshop(s) in UK, and China to attract new China academic and industry partnership and be guided by medicinal chemistry at Dundee and antibiotic discovery industry experts during the collaboration to prioritise chemical approaches.

Two PDRAs are required, based at Harwell, one to support protein production and crystallography the other in silico modelling and in support of the X-ray crystallography-based FBLD platform. They will be involved in construct designing, cloning, protein production and purification, crystallization, Xchem fragment screening and data processing and analysis chemical docking and design. Moreover, the PDRAs will be involved in Harwell-based workshops and ongoing support.

Planned Impact

Antibiotics have been a mainstay of human healthcare for over 70 years. However, the inexorable spread of antibiotic resistance limits their ability to prevent and to cure life-threatening diseases. Enduring targets for antibiotics included components of bacterial cell wall biosynthesis, in particular the targets of penicillin (e.g. penicillin binding proteins or PBPs that synthesise peptidoglycan) and protein biosynthesis (e.g. RNA polymerase). We will focus upon these as well validated targets that new mechanistic and structural insight can be used to develop novel inhibitors alongside new approaches to identify inhibitors that may simultaneously knock of penicillin resistance (penicillin destroying enzymes, beta-lactameses) and inhibit PBPs. This search for new non-lactam antibiotics that target PBPs that also target beta-lactamases, if successful, would side-step decades of beta-lactamase evolution in one leap.

In addition we will identify chemical probes to help validate novel cell wall and novel anti-virulence targets. This process of validation is crucial for the global AMR research community to best understand where research priorities should be. This information is also vitally important to help inform global pharma.
This proposal brings together a globally unique group of recognised world leaders in complementary aspects of bacterial biochemistry, chemistry, genetics, physics and physiology in the area of peptidoglycan metabolism, structure and architecture. Our aim is to build from this proposal a nationally integrated, multi-centre, multidisciplinary programme of research to address the critical and unresolved understanding of PBPs in relevant Gram negative and Gram positive pathogens that is essential for future antibiotic discovery.

This will extend key competencies and capabilities of academia to support and engage effectively with the global biotechnology and pharmaceutical sector. As such the project will have diverse impacts within the UK and internationally. Some of the expected impacts will be relatively short-term (i.e. within the life-time of the grant itself) while we expect others to be medium- to long-term in nature. The PI and industry advisory panel, populated with world leading industry consultants, with recognised track records in antibiotic discovery, and senior representatives from current pharma partners, will ensure that impact activities are considered and acted upon throughout the project. This will provide exceptional opportunities to engage with industry and through workshops to expand this across the wider academic community.

Extension of a unique multidisciplinary multi-institutional training environment in cell wall biosynthesis to a wide cohort of students will be another important impact, including the development of training across the antibiotic discovery pipeline with a clear industry focus and specialist input from our industry consultants. The results will be of widespread academic and pharmaceutical interest, because of almost all efforts to date on PBP inhibition have focused on beta-lactams.

We have unprecedented support from global pharma, from PhD support to running screens and providing access to probe compounds, and engaging as members of our exceptional scientific advisory panel. All have a strong interest in using the pre-competitive information that will be generated. To help achieve this engagement we have well defined objectives and routes for further exploitation.

Publications

10 25 50

 
Title Science as art program China 2017 
Description At the prestigious ART LABOR gallery in Shanghai's Jing'an District on 24 October, 12 select students from leading Shanghai universities were led by renowned British artist Sarah Butterfield in a masterclass on the subject of 'How thinking like a scientist has helped me as an artist'. Utilising images and concepts drawn from different scientific disciplines, the students created original artworks in charcoal and oils, drawing on Ms Butterfield's own approach to observation and the theory of colour. Led by the Arts and Humanities Research Council in partnership with the Research Councils UK China Office, the masterclass was supported by a host of science and creative industries bodies in the UK and China, including a number of AHRC's fellow research councils. 
Type Of Art Artistic/Creative Exhibition 
Year Produced 2017 
Impact Uk- China research and art collaboration use of patterned coloured crystals from our CHNUK collaborative study as the major exhibit (see web link - rear wall) 
URL http://www.ahrc.ac.uk/newsevents/news/science-as-art-masterclass-and-exhibition-in-china/
 
Description Attendance at All Parliamentary Group for AMR
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact APPG on Antibiotics - 'How close are we to meeting the urgent need for new antibiotics?'
 
Description Coventry General Charities
Amount £157,000 (GBP)
Organisation General Charity of the City of Coventry 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2018 
End 09/2022
 
Description Newton UK china ANMR hubs
Amount £3,000,000 (GBP)
Funding ID MR/S014934/1 
Organisation University of Warwick 
Sector Academic/University
Country United Kingdom
Start 01/2019 
End 12/2021
 
Description Dundee Drug Discovery Unit 
Organisation University of Dundee
Department Drug Discovery Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution Dundee Drug Discovery Unit
Collaborator Contribution Future chemistry and NMR screening support
Impact International collaboration is the future of antibiotic discovery - this was embedded within the recent Radio 4 AMR drama 'Resistance' http://www.bbc.co.uk/programmes/b08hylsn
Start Year 2016
 
Description H3D drug discovery University of Cape Town 
Organisation University of Cape Town
Country South Africa 
Sector Academic/University 
PI Contribution Input of reagents assays and protein structures
Collaborator Contribution Input of medicinal chemistry know-how and chemical matter
Impact Interpersonal exchange of postdocs and to be PhD students
Start Year 2017
 
Description SME collaboration 
Organisation Argenta Discovery
Country United Kingdom 
Sector Private 
PI Contribution Collaboration with Antimicrobial Discovery Solutions not Argenta Discovery
Collaborator Contribution Knowledge transfer
Impact Multidisciplinary microbiology, biochemistry structural biology chemistry
Start Year 2017
 
Description Vernalis 
Organisation Vernalis
Country United Kingdom 
Sector Private 
PI Contribution Knowledge transfer bidirectional
Collaborator Contribution Access to a fragment based discovery training course for students and post docs
Impact Training
Start Year 2016
 
Description 10 Downing Street 2018 Chinese New Year Celebrations 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Invitation from the PM to attend event to showcase UK China collaborative AMR research
Year(s) Of Engagement Activity 2018
URL https://www.gov.uk/government/news/pm-hosts-chinese-new-year-reception-at-downing-street
 
Description BBSRC Strategic Partnership Visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact A team from the BBSRC executive visited the University on 10 May 2018 as a part of our
strategic partnership. More than 70 Warwick staff from various departments joined in
the open sessions.

Presentation of Research and Virtual Reality system
Year(s) Of Engagement Activity 2018
URL https://warwick.ac.uk/fac/sci/lifesci/intranet/staffpg/support/comms/slsupdate/sls_update_june_2018....
 
Description China UK People to People Exchange Royal Society December 6th 2017 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact As PI for the CHNUK research grant I represent the wider UK-China AMR programme at the UK China People to People Dialogue in London on 6 December at the Royal Society.

There was space for 15 of the highest profile collaborations and the FCO recommended the programme as a whole, but specifically that the CHNUK to be featured. As described by the FCO at the time "The programme is obviously a key part of the UK's current portfolio of research collaborations, and the exhibition stands need to be visual. A lot of the other stands will be full of robots and other toys so I need something that would stand out, having seen some of the X-ray crystallography images I thought this might be eye catching enough.

There will be a walk through of the exhibition by UK and Chinese Ministers, including Madame Liu Yandong and hopefully Greg Clark on their way in to the building and hopefully they will stop and talk to several of the exhbitors and do photos but we don't know what will catch their eye just yet. You would be free to join the rest of the event after the Ministers have left, perhaps a colleague could attend the stand during the breaks etc."
Year(s) Of Engagement Activity 2017
URL https://www.gov.uk/government/topical-events/uk-china-high-level-people-to-people-dialogue-2017
 
Description MRC Milennium Medal Showcase of AMR research Palace of Westminster 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Presentation of MRC and RCUK funded AMR research to Peers and Politicians at the Palace of Westminster as part of the 2018 MRC Millennium Medal Award event
Year(s) Of Engagement Activity 2018
URL https://www.youtube.com/watch?v=n2Z6Xxs8aA0
 
Description Pint of Science public outreach 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Pint of Science is an annual science festival that takes place every May and brings researchers to your local pub to present their scientific discoveries.
Year(s) Of Engagement Activity 2018
URL https://pintofscience.co.uk/event/life-is-the-name-of-the-game
 
Description Public Science Event Warwick University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact On Thursday 26 April 2018, the School of Life Sciences hosted its fourth public
science evening of the 2017/18 academic year (the ninth since the programme
began in 2016). This evening was a panel discussion focussing on three topics of
interest, highlighted by the public from previous public science evenings. These
were: Epigenetics, Environment & Sustainability and Medical Microbiology
Year(s) Of Engagement Activity 2018
URL https://warwick.ac.uk/fac/sci/lifesci/intranet/staffpg/support/comms/slsupdate/sls_update_june_2018....
 
Description Radio 4 3 part drama production 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Radio drama highlighting factors driving antibiotic resistance and global consequences - raising public awareness at the National level
Year(s) Of Engagement Activity 2017
URL http://www.bbc.co.uk/programmes/b08g7y1l
 
Description UKRI Superheroes vs Superbugs live at the Science Museum 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact On 25 April, leading researchers from the MRC and UK research councils will join the Science Museum's free, adults-only, late opening of the Superbugs: The Fight for Our Livesopens in new window exhibition. The exhibition, which is sponsored by UKRI, looks at the causes and challenges of antimicrobial resistance (AMR), and why previously effective drugs are no longer winning the battle against some infections.
Mega Magnification - Be transported into the hidden world of bacteria. Use VR to shrink yourself, meet mighty bacterial proteins and reveal their microscopic secrets.
Year(s) Of Engagement Activity 2018
URL https://mrc.ukri.org/news/browse/ukri-superheroes-vs-superbugs-live-at-the-science-museum/
 
Description United Nations General Assembley 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Invited to attended AMR working group presentations
Year(s) Of Engagement Activity 2016
URL http://www.un.org/pga/71/event-latest/high-level-meeting-on-antimicrobial-resistance/