Bacteriophage and Antibiotic Resistance: a Mathematical and Imaging Approach (C-DIP enhancement)

Lead Research Organisation: University of Exeter
Department Name: Biosciences

Abstract

While scientific research was usually conducted in centuries past by loan, gentleman scientists,modern research is different. It needs people with different skills and different scientific trainingto come together with a common vision to solve a common problem.Think of a large task, like building a plane. It needs control engineers, material scientists,software engineers, fluid dynamicists, test pilots, to name but a few of the types of peoplewho might be involved. Ask yourself, how does a software engineer with a training in thedevelopment of programming languages, say, talk to a metallurgist or chemist in order tosolve the problems they encounter on a daily basis in the aeronautical industries?Of course, in industrial contexts one answer lies in training as the path to constructing a planeis largely known. But in science, there are no well-developed training programmes that allowpeople to come together to solve the big problems, we might not even know what people toput together in order to solve them. So, we need patience, lots of it, and trust but we also need funding and helpwith the process of getting ideas from one field to permeate into another.Often, as a mathematician, when I express my ideas to biologist colleagues, they first tell methat I am mad, that I must be wrong because there are experimental results from decadespast that contradict my thinking. However, over time, with enough coffee and patience we canexplore each others viewpoint and crystalise and then distill the idea down to its bare minimum. We thensee whether there really is something that mathematical thinking can bring to biology, or to physicsor chemistry.This can be a personal and painful process, but it is worthwhile in that the amalgam of two sets of ideaslead to new independent thinking and new ideas. However, this is not a route or an approach commonly funded by research councils. In this case EPSRC have been explicit in their desire for research themes that aimto bridge these gaps between disciplines and to really foster avenues of communication where few ornone currently exist. The funding associated with this award will be put to good use to create alively and relaxed research environment where we can express our mad ideas and see if they can beput to good use to solve important problems in a range of fields that spans physics, biology and mathematics.If the recent past is a guide to the near future, we expect this endeavour will lead to a number of new and important scientific insights.

Planned Impact

An impact summary is not required, according to the following text in an email I received from Shaz Kahn/Zoe Brown: ...Please do not submit an impact plan, a project plan/Gantt chart or any nominated reviewers.

Publications

10 25 50
 
Description This award considered viral and antibiotic resistance among species of bacteria, with several outputs. Some outputs are theoretical, producing new principles for infectious disease treatments by studying general principles that may even have applications to how we view cancer. The core idea is that the evolution of resistance (encoded in DNA-based SNPs but also larger chromosomal mutations) can alter multi-drug interactions (like drug synergy) through time. We then showed how to exploit some of these principles in order to design more potent therapies than ones currently in use that do not account for the evolutionary trajectories that arise during treatment. One typical treatment involves the use of two drugs in a manner that cycles between them to optimise the killing rate of bacteria inside a patient undergoing treatment. Many of the theories and ideas are lab-based and data is not, as yet, available for real world scenarios but discussions are underway with clinicians as to how to apply these ideas to hard-to-treat infections. Of particular interest is sepsis where we are working with clinical groups to develop new ways of treating with antibiotics and phage. The key idea there is phage resistance that can develop in bacteria: does this happen during a patients infection and, if so, how can that be mitigated? We have developed imaging algorithms to elucidate new ways of assessing how bacterial pathogens interact with phage and we are now applying those data-driven ideas to isolates from clinical patients in critical care.
Exploitation Route The short answer is In the synthetic phage community, in antibiotic pharmacology, indeed in any field of science and medicine where people are seeking evolution-aware treatments of infectious disease. So new treatments that cycle antibiotics rationally, new ways of phenotyping resistant phage during treatment, new genomic analysis pipelines for chronic bloodstream infections and new data=driven mathematical theories applied to clinical strains will all yield long-term patients benefits. This is clear from our ongoing interactions with infection medics who work in hospitals from Australia to Nigeria to the UK.
Sectors Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description The findings from the award have been used in a myriad of ways. First, outcomes informed the design of mathematical models in collaboration with AstraZeneca Oncology Modelling unit with whom we have worked to better understand both anti-bacterial and and anti-cancer chemotherapies. This is a large and ongoing project that is not possible to summarise in this box but has results in AZ part-funding in my laboratory. The key output is desired elsewhere in Research Fish but we have used mathematical techniques to find similarities between cancer and infection treatments whereby both give 'boosts' to cell growth during treatments. This is something that needs to be avoided, after all the job of a treatment molecule, like an antibiotic, is to kill cells not to boost their growth. However, we have shown that are there contexts in which boosts occur, to the potential detriment of treatment, and we have elucidated conditions under which boosts occur, both in theory and in the lab. As an 'industrial output' of this award we are now at the point fo finalising a low-cost biomedical device akin to a spectrophotometer that measures antibiotic resistance properties of bacteria in a high-throughput fashion, this means we can assess those properties much more cheaply and much more rapidly than was possible in the past. The device we make is very low cost, so where these retail at a round $100,000 for a hospital, we can fabricate equivalent technology for around £300, by exploring the right kind of modular parts and data-driven analyses. We are now in the process of securing IP protection and are patent pending, but we also have a commercialisation strategy for the device once lab trials and subsequent re-designs are finished. Interestingly, UK and US schools have shown interest in using this as part of their biology classes and we are trying to make more devices to service that need. The project has developed to the point where we can make devices that are competitive with commercial ones (as purchased by our lab) in terms of data quality. We even have our first pre-orders to use them in lab and school contexts, we are now in the process of finalising the manufacturing pipeline so that we can assure quality, both of hardware and data, between different device builds.
First Year Of Impact 2017
Sector Chemicals,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic