The Physics of Antimicrobial Resistance

细菌对抗生素产生抗药性(抗菌素耐药性，AMR)是一个全球性的挑战，有可能破坏现代医学的许多进步，从而带来巨大的人力和经济成本。AMR是一个多方面的问题，在这个问题中，发生在许多不同长度和时间尺度上的过程相互作用，导致耐药细菌的出现。为了对这种复杂性有一个预测性的理解，我们将采取跨学科的方法，将定量实验和数学物理与尖端微生物学、生物化学和传染病生物学结合在一起。细菌通过基因突变和基因获取而产生抗药性，这必然会导致生理变化，包括在抗生素胁迫下明显的持续生长。通过更好地了解这些变化的物理性质，我们的目标是揭示与AMR相关的可开发的适应成本，即细菌变得更脆弱的方式，作为它们对特定抗生素产生抗药性的代价。我们的计划将专注于针对抗生素的细胞壁耐药性机制。细菌有一个细胞壁来维持它们的生命，细胞壁是由肽聚糖制成的，肽聚糖是一种不是由人类产生的物质。青霉素等以合成肽聚糖为靶点的抗生素在临床上具有重要意义。对这些抗生素耐药的细菌菌株，如甲氧西林耐药金黄色葡萄球菌(“医院超级细菌”)和碳青霉烯耐药肠杆菌科(CRE)被认为是全球威胁。将我们的努力集中在这些世卫组织优先生物体上，为该计划提供了一条直接的转化途径。为了在理解上取得突破，我们将采取多管齐下的方法。我们将结合尖端原子力显微镜、根据需要开发新仪器、最先进的生物化学和机械建模来找出细菌对特定抗生素敏感和耐药之间的细胞壁差异。化学、分子组织和物理性质之间的关系是材料物理的核心问题，在这里，通过将定量实验与分子建模相结合，我们将提供对细胞壁以及阻力如何改变的预测性理解。其次，我们将集中讨论AMR如何改变细菌生理学。例如，MRSA已经获得了一种新的细胞壁合成酶，绕过了对β-内酰胺类抗生素(如青霉素)天然的抗生素敏感靶标的需要。我们已经证明，仅有这种酶是不足以产生抗药性的；需要对转录机制(RNA聚合酶)进行额外的改变。使用单分子和统计物理方法，我们将适应和发展这个问题，再加上分子生物学和生物化学，我们将获得对这些相互作用的相互作用网的理解，这些相互作用的网络驱动耐药性进化并表征AMR生物体。第三，我们将探索AMR在不同条件下如何影响细菌适应性，使用基于体外实验和体内实验的最先进的微流体，以确保与活宿主的真实条件相关。因此，我们将找到AMR生物容易受到靶向治疗的条件。为了实现我们雄心勃勃的目标，我们组建了一个独特的团队，成员包括原子力显微镜、单分子生物物理学、微流体学和理论物理、革兰氏阴性和革兰氏阳性细菌微生物学以及转录生化方面的专家。采用综合方法，该项目将提供对AMR的新理解，具有直接的临床意义。

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.