Cross-scale prediction of Antimicrobial Resistance: from molecules to populations.

Lead Research Organisation: University of Warwick
Department Name: Mathematics

Abstract

Antimicrobial Resistance (AMR) is a major threat to human health, dramatically reducing the effectiveness of drugs that have been a substantial component of medical treatment for decades. Traditionally the study of AMR has been led by Medical and Life Science researchers. However, we believe that to effectively halt the rise of AMR in the population requires the combined resources of Mathematical, Engineering, Physical, Chemical, Medical and Life Sciences, in highly interdisciplinary ventures. Moreover, we feel that the quantitative and predictive skills of EPSRC remit sciences is key to creating a step-change in the study of AMR in terms of: understanding mechanisms of AMR, prediction of potential novel antibiotic targets and methods to contain and control AMR spread.

We have identified five key areas of research in Warwick in which we already have interdisciplinary strengths and which will form key themes of our application:
1) Cell Wall Assembly. The assembly of the cell wall is one of the major targets for antibacterial drug action, and brings together key researchers in Chemistry and Life Sciences in addition to strong industry collaboration.
2) Bacterial Cell Division. Closely linked to the cell wall assembly proteins are the range of accessory proteins providing temporal interactions, force generation and regulatory capacity as well as substrate interactions for the PBPs that are necessary for bacterial cell division.
3) Antimicrobial Discovery. Identification of potential novel antimicrobial actions is a key element in combating the increase in AMR. Warwick is involved in the development of an unusually diverse range of novel antimicrobial systems, focusing on discovery, development and mechanism of potential targets.
4) Bacterial Genomics. Sequencing technologies, particularly high-throughput sequencing, have already made a considerable impact on medical microbiology. Warwick researchers are well placed to translate their experience into the understanding of AMR spread in health-care settings.
5) Public Health Epidemiology. An understanding of public-health is central to a wider understanding of how novel scientific discovery can be translated into applied health benefits. Mathematics, Life-Sciences and Medicine are all individually strong in this area.
In turn these subject areas are supported by Warwick's recognised expertise in mathematical modelling (both population and systems biology), imaging techniques and diagnostics.

This proposal has three main mechanisms through which the gaps between these subject areas will be bridged and productive interdisciplinary collaborations initiated.
1) Short term discipline-hopping fellowships. Utilising the highly successful and cost-effective fellowship model developed by the Warwick Institute of Advanced Study, we will recruit junior post-doctoral researchers to cross-departmental positions.
2) Focused cross-disciplinary meetings. Such meeting will take a variety of formats, but will form the natural interface between Warwick academics, industry and public-health researchers, and academics from other institutions. We intend to host vacation schools, problem-solving workshops and study-groups, together with larger research symposia. Potential early meetings could focus on "Passage Across the Cell Membrane", "Bacterial Cell Division" and "AMR in healthcare settings".
3) Visiting Fellowships. Although we believe Warwick is unique in the breadth of skills it supports, there are obviously many specialist areas where we simply do not possess the necessary expertise. To bridge this skills gap we will invite a select number of senior academics to short-term (3-6 month) visiting fellowships.
4) Pump Priming. This will be open to all Warwick researchers and will be used to increase Warwick's capacity and capability to undertake world-class, innovating and exciting research in AMR.

Planned Impact

SCIENTIFIC IMPACT
Key to the scientific impact of the proposed project is the development of mechanisms to ensure a quantitative and predictive approach will be integrated into all our research and training activities in AMR. Existing initiatives at Warwick have already facilitated pair-wise collaborations, but these will be integrated into a community aware of where strengths are to be found in AMR research at Warwick to ensure that the whole landscape is addressed. We have structured the activity in terms of: SHORT-TERM FELLOWSHIPS to bridge gaps from one discipline to another with well-defined research goals; CROSS-DISCIPLINE RESEARCH MEETINGS focused onto a specific aspects of AMR; a small number of VISITING FELLOWS will support the development of AMR in Warwick; and PUMP PRIMING to kick-start cross-departmental collaborations leading to new funding applications.

ENHANCED SKILLS PROVISION
The fellows will benefit from 1-1 training in their new discipline to ensure they can work to fill gaps. They and the wider Warwick and external community will gain enhanced career prospects as well as the immediate technical skills gain from the Vacation Schools which will be designed to teach core EPS skills that we consider essential to addressing the AMR problem including biophysical and mathematical techniques. We will also run Schools to teach physical scientists the required biology for them to be able to develop new methods and integrate their expertise into AMR research projects. Thus the early career researchers involved in the Network will learn to think and communicate in different scientific languages to the net benefit of AMR research. We have extensive experience of this type of training from having delivered the life sciences interface MOAC DTC MSc and PhD training programmes for 12 years.

OUTREACH PLANS
AMR is a topic that receives considerable media attention. All members of the network will enhance their current outreach activities by bringing elements of cross-disciplinarity and the importance of EPS approaches to solving what is arguably one of the most significant societal health problems. At this stage we envisage having a general public component to the Annual Symposia, including AMR in our extensive schools outreach programme to target 'the next generation', make regular press releases, be available for interviews etc. as required. We will liaise closely with Warwick's effective press office to achieve maximum effect for our efforts. Training will be provided to the early career researchers first for their own web sites and effective scientific communications and then for communication to the general public including via giving interviews, interacting with radio, TV or video programmes, presenting science on the web, making press releases, giving 'elevator pitches' generally addressing different non-scientific audiences

INDUSTRY INVOLVEMENT
A current major problem in antimicrobial drug development is the inability of pharmaceutical companies to drive sales to recoup research costs due to the fact that widespread over-use of antimicrobials has fuelled the problem of resistance development. Various strategies have been proposed to delinkage profit from sales e.g. by the availability of patent buy-outs or strategic holding of new not-for-sale drugs in government reserves for future. We will involve our industry collaborators in all aspects of the network from co-supervising fellows, to helping deliver workshops and attending them, joining research meetings to insure an industrial perspective since any solution to AMR will ultimately require significant industrial involvement whether it is at the diagnosis or treatment end of the process. We anticipate having at least one of the visitors being from industry to facilitate cross-sector communication.

Publications

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Chellan P (2018) Organometallic Conjugates of the Drug Sulfadoxine for Combatting Antimicrobial Resistance. in Chemistry (Weinheim an der Bergstrasse, Germany)

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Chen F (2018) Biguanide Iridium(III) Complexes with Potent Antimicrobial Activity. in Journal of medicinal chemistry

 
Description - Achieved substantial commitment from senior EPS academics (in Chemistry, Physics, Engineering and Maths) to attend AMR- related events and be involved with many of our 'Bridging the Gaps' funding opportunities in collaborative links with Life Sciences and Medicine.
- Strengthened links with prominent external partners including: Public Health England, NIHR Clinical Research Network, University Hospitals Coventry & Warwickshire, Royal Society of Chemistry
- Exploited joint opportunities with other initiatives across campus such as the Global Research Priorities and the Institute of Advanced Studies to raise institutional buy- in
- Improved links with other universities including Bridging the Gaps network
- Promoted AMR to multiple EPS researchers (at all levels) with limited prior exposure to the field
Exploitation Route - More engaged members of the public and pupils on AMR and interdisciplinary solutions to tackle the issue
- Improved skills provision and retention of Early Career Researcher talent in the AMR field.
Sectors Education,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Created a 'Warwick AMR' online and social media presence, leading to dialogue and cross-promotion with the online community of AMR researchers, charities, funders and drug discovery initiatives such as the Longitude Prize. Meeting attendee surveys have indicated that Twitter was a successful promotion platform. Engaged members of the public and pupils on AMR and interdisciplinary solutions to tackle the issue Created educational and outreach tools and resources (Virtual Reality Protein Explorer, AMR Classroom Workbook, publication in Warwick Journal of Education). The Virtual Reality Protein Explorer has been exhibited at the university, at the Houses of Parliament, at the Royal Society and internationally at Chinese universities. Generated IP in the form of records of invention (ProteinViewer 1.0 Software; PDB2Movie Website) and patents (Covington; Fullam) Set up a cross-campus AMR screening facility that is financially self-sustaining and attracting customers from academia and beyond (over 40 projects in its first year)
First Year Of Impact 2016
Sector Education
Impact Types Societal,Economic

 
Description Accelerate CHNUK AMR discovery: Establishing joint China/UK training and research platforms enabling highthroughput fragment based inhibitor discovery
Amount £717,518 (GBP)
Funding ID MR/P007503/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 07/2016 
End 06/2019
 
Description CHNUK: Integrated platforms from science to policy in response to antibacterial resistance
Amount £1,999,214 (GBP)
Funding ID MR/S014934/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2019 
End 12/2021
 
Description Chicken or the Egg: Is AMR in the Environment Driven by Dissemination of Antibiotics or Antibiotic Resistance Genes?
Amount £352,504 (GBP)
Funding ID NE/N019857/1 
Organisation Natural Environment Research Council 
Sector Public
Country United Kingdom
Start 06/2016 
End 05/2019
 
Description Novel inter-disciplinary approaches for identifying and tackling the spread of AntiMicrobial Resistance through Environmental pathways in PAKistan
Amount £80,472 (GBP)
Funding ID MR/R015058/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2017 
End 03/2018
 
Description Tools and Reagents for Next Generation Inhibitor Discovery in Peptidoglycan biosynthesis
Amount £455,666 (GBP)
Funding ID BB/N003241/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 03/2016 
End 07/2018
 
Description Using next generation sequencing to reveal human impact on aquatic reservoirs of antibiotic resistant bacteria at the catchment scale
Amount £488,611 (GBP)
Funding ID NE/M011674/1 
Organisation Natural Environment Research Council 
Sector Public
Country United Kingdom
Start 06/2015 
End 12/2018
 
Description Antifungal resistance and epidemiology of Candida glabrata isolates in critically ill patients using novel genomic sequencing technology 
Organisation University of Birmingham
Department Department of Public Health, Epidemiology & Biostatistics (PHEB)
Country United Kingdom 
Sector Academic/University 
PI Contribution We plan to study target isolates from critically ill patients admitted to the University Hospital Birmingham and Heartlands Hospital Birmingham (identified by Dr Miruna David and Dr Abid Hussain respectively). By sequencing 30 isolates (initially using the well-established Illumina technology) we seek to obtain a broad picture of the genetic diversity of C. glabrata isolates and of key mutations/SNPs associated with resistance to antifungal drugs. DNA Extraction: ? This is a critical step in the experiment process and particularly novel with regards extracting high quality fungal DNA for next generation sequencing. The process will be lead experimentally by one of the University of Warwick collaborators (Chrystala Constantinidou), but will involve collaborative input from all sites as there is extensive interest/experience with this process.
Collaborator Contribution Data analysis will be performed by Dr Owen Lancaster but additionally involve collaboration and final interpretation by all members of the team. Laboratory staff and bioinformatics analysis time: experimental work and data analysis will be carried out at both Public Health England and University of Warwick sites and will require additional costing in order to carry out the proposal. However all other members of the team are prepared to take no salary due to the exciting nature and potential benefit to AMR it could offer.
Impact This is a new collaboration, with the following disciplines: Chrystala Constantinidou: Microbial genomics Chris Dowson: Microbiology Miruna David: Consultant Microbiologist Owen Lancaster: Public Health bioinformatician
Start Year 2017
 
Description Towards personalised empirical antibiotic guidance - a pilot study 
Organisation Birmingham Heartlands Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution Prof Matt Keeling - Maths & Life Sciences University of Warwick. Dr Keeling will work on the anonymised dataset. We hope to answer important questions relating to the use of antibiotics, and assess how this and other patient factors relate to the emergence of resistant organisms. We will use this information to create more nuanced empirical antibiotic prescribing rules. In the future we hope this project will lead to development of a system that produces individualised empirical antibiotic recommendations for certain conditions, and - in line with the NICE Antibiotic Stewardship recommendations - recognises patient safety issues and provides prescriber-level feedback on antibiotic use. Such feedback has been shown to positively influence prescribing behaviour.
Collaborator Contribution Dr Ed Moran and Dr Esther Robinson - infection specialists based at Heart of England NHS FT (HEFT). HEFT was among the first secondary care users of EPMA (electronic prescribing and medicines administration) in the UK. We have been granted to permission to use exports from the EPMA, microbiology and patient information databases (demographics, comorbidities, admission and discharge dates) for the purposes of this project - prescribing data is available from 2010 and records approximately 29,000 patients a year receiving antibiotics at the 3 hospitals operated by the Trust. We will anonymise before sharing with our University of Warwick partners.
Impact This is a new multidisciplinary collaboration: Discipline 1: Mathematics (disease modelling) Discipline 2: Infection specialists
Start Year 2017
 
Description 'Plague in Shakespeare's Time Outreach' 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact 'Plague in Shakespeare's Time Outreach'
Type: Public outreach event for children and families at The Shakespeare Fun Palace 2016
Activities: 1) Posters on the Science of Plague Transmission,

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Entry of Plague into Europe, Plague in Shakespeare's Family Tree, Modern Day Multidrug Resistant Plague; 2) Re- creation of entry of plague into Europe with interactive catapult activity; 3) Microscopes linked up to TV screens allowing general public to view slides of Gram negative vs Gram positive bacteria; 4) Plague poem competition; 5) Educational booklet
Attendees: 491
Year(s) Of Engagement Activity 2016
URL https://www.shakespeare.org.uk/explore-shakespeare/blogs/fun-palace-2016/
 
Description AMR Awareness Schools Outreach 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Aims:
- To promote science as a way of investigating and tackling important issues
-To engage pupils on the concepts underlying antibiotic resistance and antibiotic stewardship:
1) Antibiotics only kill bacteria not viruses
2) Patients should only take antibiotics if a Doctor has prescribed them
3) An antibiotic course must be completed even if the patient feels better
4) Good hand hygiene can prevent infection spread and reduce the need for antibiotics
5) Antibiotic resistance can be defined as: "When infections become untreatable because bacteria change and can no longer be killed by an antibiotic"
Year(s) Of Engagement Activity 2016
URL https://storify.com/warwick_amr/warwick-antibiotic-awareness-outreach
 
Description AMR Clinical Sandpit 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact - To enhance working relationship between Warwick, the NIHR Clinical Research Network and Public Health England
- To promote interdisciplinary work to tackle AMR
- To promote AMR to EPS-remit researchers
- To act as a catalyst for innovative ideas to tackle AMR with patient benefit in mind

Target Audience


University of Warwick EPS researchers (physics, engineering and chemistry), all UK clinicians, all UK researchers with an interest in tackling AMR


Attendees: 44
42% non-Warwick
Audience type: Entrepreneurs, UK academics, NHS consultants, Clinical Microbiologists, Antibiotic pharmacists, Public Health England staff, Clinical Research Network staff, Lay member
Disciplines: Analytical chemistry, control theory, structural biology, drug discovery, medical devices, antibiotic prescribing, behaviour change, sexually transmitted infections, genomics, bioinformatics, machine learning
Countries: UK
Institutions: Warwick, Bristol, Wolverhampton, PHE, NIHR CRN, UHCW, Heart of England NHS, City University, OpenClinical, University Hospitals Birmingham, Imperial College London, Leeds
Year(s) Of Engagement Activity 2016
URL http://www2.warwick.ac.uk/fac/cross_fac/wamic/integrate/sandpit/
 
Description Antibiotic Awareness Week SLS Outreach 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Evening of public science with talks, demonstrations and lab tours.
Year(s) Of Engagement Activity 2016
URL http://www2.warwick.ac.uk/fac/sci/lifesci/outreach/next/
 
Description MathSys Summer School 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact We said that we would help kickstart the independent scientific careers of early career researchers by providing training in EPS-remit skills. MathSys CTD, which hosted the summer school, was an ideal location for this as it brought together quantitative scientists interested in tackling real-world problems through mathematical modelling and hence provided an ideal skills base for many problems encountered in a quantitative understanding AMR.
We also said that we would continue to nurture our working relationships with Public Health England. At the Summer School, Clinical data was provided and explained by Dr Julie Robotham (PHE), who set the challenges to the attendees.
Year(s) Of Engagement Activity 2016
URL https://www2.warwick.ac.uk/fac/cross_fac/wamic/integrate/summerschool/