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

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.

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.