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

抗菌素耐药性(AMR)是对人类健康的一大威胁，它极大地降低了几十年来一直是医疗治疗重要组成部分的药物的有效性。传统上，AMR的研究一直由医学和生命科学的研究人员领导。然而，我们认为，要有效地阻止AMR在人口中的上升，需要将数学、工程、物理、化学、医学和生命科学的资源结合在一起，进行高度跨学科的冒险。此外，我们认为EPSRC项目科学的定量和预测技能是在以下方面创造AMR研究阶段性变化的关键：了解AMR的机制、预测潜在的新抗生素靶点以及控制AMR传播的方法。我们已经确定了沃里克的五个关键研究领域，在这些领域我们已经拥有跨学科的优势，并将形成我们应用的关键主题：1)细胞壁组装。细胞壁的组装是抗菌药物作用的主要目标之一，除了强大的行业合作外，还聚集了化学和生命科学方面的关键研究人员。2)细菌细胞分裂。与细胞壁组装蛋白密切相关的是一系列辅助蛋白，为细菌细胞分裂所必需的PBPs提供时间相互作用、力产生和调节能力以及底物相互作用。3)抗菌药物的发现。确定潜在的新的抗微生物作用是抗击AMR增加的关键因素。华威参与了一系列异常多样化的新型抗菌系统的开发，专注于潜在靶点的发现、开发和机制。4)细菌基因组学。测序技术，特别是高通量测序，已经对医学微生物学产生了相当大的影响。华威大学的研究人员很好地将他们的经验转化为对医疗保健环境中AMR传播的理解。5)公共卫生流行病学。对公共健康的理解是更广泛地理解如何将新的科学发现转化为实用的健康益处的核心。数学、生命科学和医学都是这一领域的强项。反过来，这些学科领域又得到了华威在数学建模(种群和系统生物学)、成像技术和诊断方面公认的专业知识的支持。这项建议有三个主要机制，通过这些机制，这些学科领域之间的差距将被弥合，并启动富有成效的跨学科合作1)短期学科跳槽奖学金。利用华威高等研究院开发的非常成功和具有成本效益的研究金模式，我们将招募初级博士后研究人员担任跨部门职位。2)有重点的跨学科会议。这样的会议将采取多种形式，但将在华威学者、工业和公共卫生研究人员以及其他机构的学者之间形成自然的接口。我们打算举办假期学校、解决问题的研讨会和学习小组，以及更大规模的研究研讨会。可能的早期会议可能集中在“穿过细胞膜的通道”、“细菌细胞分裂”和“医疗环境中的AMR”。3)访问奖学金。尽管我们相信华威在其支持的技能广度上是独一无二的，但显然有许多专业领域我们根本不具备必要的专业知识。为了弥补这一技能差距，我们将邀请一些精选的资深学者参加短期(3-6个月)的访问奖学金。4)泵启动。这将向所有华威研究人员开放，并将用于提高华威在AMR方面进行世界级、创新和令人兴奋的研究的能力和能力。

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.