The Physics of Antimicrobial Resistance

Lead Research Organisation: University of Sheffield
Department Name: Physics and Astronomy

Abstract

The development by bacteria of resistance to antibiotics (antimicrobial resistance, AMR) is a global challenge that threatens to undermine many of the advances of modern medicine, with consequential massive human and financial costs. AMR is a multi-faceted problem in which processes occurring over many different length and timescales interact, leading to the emergence of resistant bacteria. To obtain a predictive understanding of this complexity we will take an interdisciplinary approach, bringing together quantitative experimental and mathematical physics with cutting-edge microbiology, biochemistry and infectious disease biology. Bacteria become resistant through genetic mutation and gene acquisition which inevitably leads to physiological changes, including the obvious sustained growth when under antibiotic stress. By better understanding the physical nature of these changes we aim to reveal exploitable fitness costs associated with AMR, i.e. ways in which the bacteria become more vulnerable as the price they pay for becoming resistant to particular antibiotics.

Our programme will focus on resistance mechanisms to cell wall targeting antibiotics. Bacteria have a cell wall that keeps them alive which is made from peptidoglycan, a material not produced by humans. Antibiotics such as penicillin which target the synthesis of peptidoglycan are clinically critically important. Bacterial strains resistant to these antibiotics, such as methicillin resistant S. aureus (the "hospital superbug" MRSA) and carbapenem-resistant enterobacteriaceae (CRE) are recognised as global threats. Concentrating our efforts on these WHO priority organisms provides a direct translational route for the programme.

To provide breakthroughs in understanding we will take a multi-pronged approach. We will combine cutting edge atomic force microscopy, development of new instrumentation as required, state-of-the-art biochemistry and mechanical modelling to find how the cell wall differs between bacteria sensitive and resistant to particular antibiotics. The relationship between chemistry, molecular organisation, and physical properties, is a problem at the heart of materials physics, and here, by correlating quantitative experiments with molecular modelling we will provide a predictive understanding of the cell wall and how it is changed by resistance. Secondly, we will concentrate on how AMR alters bacterial physiology. For example, MRSA has acquired a new enzyme for cell wall synthesis, circumventing the need for the native, antibiotic sensitive target of beta-lactam antibiotics (such as penicillin). We have shown that this enzyme alone is not enough to be resistant; there needs to be additional changes to the transcription machinery (RNA polymerase). Using single molecule and statistical physics approaches that we will adapt and advance for this problem, coupled with molecular biology and biochemistry, we will gain an understanding of these interconnected webs of interaction that drive resistance evolution and characterise AMR organisms. Thirdly, we will explore how AMR impacts bacterial fitness under different conditions, using a combination of state-of-the-art microfluidics based in vitro experiments with in vivo experiments to ensure relevance to the real conditions in a living host. Hence we will find conditions under which AMR organisms are vulnerable to targeted treatments.

To reach our ambitious goals we have brought together a unique team with experts in atomic force microscopy, single molecule biophysics, microfluidics and theoretical physics, in the microbiology of Gram negative and Gram positive bacteria, and in the biochemistry of transcription. Taking an integrated approach, the project will provide a new understanding of AMR with direct clinical relevance.

Planned Impact

The impacts of this Programme our exceptionally wide ranging. AMR is a critically important global health challenge and our Programme aims to develop new insights and understanding that will directly impact human health nationally and internationally. The pharmaceutical industry is an important sector of the UK economy, and our project has the potential to have positive impact in this area also. To reach our ambitious scientific goals we will develop new techniques and approaches which will be of wider application and hence commercial value, and we will aim to exploit these possibilities through the project. We will train PDRAs in cutting edge interdisciplinary science which will have long term impact on their careers, and publicise our work and approach to the public to help inspire the next generation of researchers. Below we provide more detail on these specific areas.

Health in our society: Antibiotics are a cornerstone of modern medicine, allowing treatment of infections but also enabling many of the other treatments that we take for granted, such as chemotherapy, elective surgery, etc., as antibiotics prevent complications. AMR poses an extraordinary threat the potential impact of which is hard to over-state. Our Programme, by taking an interdisciplinary approach that brings together the predictive capabilities of theoretical physics with cutting edge biology and biophysics, provides an opportunity to make a real difference to how we approach antibiotic stewardship and how we treat AMR.

The pharmaceutical industry: The Programme team are exceptionally well connected across the UK and wider pharmaceutical industry. SF was founding director of a S. aureus vaccine company, Absynth Biologics Ltd. and is well placed to further exploit opportunities as they arise. WV and NZ work closely with Demuris Ltd, a Newcastle based drug discovery company, on potential new antibiotic targets. Our work may also reveal opportunities to re-purpose existing drugs to exploit AMR induced fitness changes. Hence our Programme will contribute to the re-invigoration of the UK pharmaceutical industry.

New techniques and approaches: Our Programme will use and where necessary develop cutting edge techniques for studying bacteria across scales from individual molecules to host organisms. Our target is AMR, but these approaches will doubtless have wider applicability, and we will ensure that as wide as possible an audience is reached. JH is highly experienced in commercialising opportunities within AFM, having founded the successful silicon surface inspection company Infinitesima Ltd., and we are well placed to maximise impact in this area.

Our Programme will be world leading example of interdisciplinary research, spanning multiple length and timescales and using an exceptionally wide range of complementary approaches. The PDRAs involved in the project will gain a unique set of skills which will make them highly employable and help to fulfil the UK requirement for scientists capable of applying quantitative approaches to biological systems and data. We will also showcase the Physics of Life Programme as an example of the best that interdisciplinarity can bring to science. We will impress on the next generation of potential researchers, teachers and industrial leaders, how they need not be constrained by traditional discipline boundaries but can be driven by the desire to understand how life works using whatever tools and approaches are necessary.

Publications

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