The Physics of Antimicrobial Resistance

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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.