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

抗生素耐药性的跨尺度预测：从分子到群体。

• 批准号: EP/M027503/1
• 负责人: Matthew Keeling
• 金额: $ 64.32万
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FM027503%2F1
• 关键词: Cross; scale; prediction; Antimicrobial; Resistance

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.

抗菌素耐药性（AMR）是对人类健康的主要威胁，它大大降低了几十年来作为医疗重要组成部分的药物的有效性。传统上，抗微生物药物耐药性的研究一直由医学和生命科学研究人员领导。然而，我们认为，要有效遏制人口中抗菌素耐药性的上升，需要在高度跨学科的企业中综合利用数学、工程、物理、化学、医学和生命科学的资源。此外，我们认为EPSRC研究领域的定量和预测技能是在AMR研究中创造一个阶段性变化的关键：了解AMR的机制，预测潜在的新型抗生素靶点以及遏制和控制AMR传播的方法。我们已经确定了华威大学的五个关键研究领域，我们已经在这些领域拥有跨学科的优势，这些领域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，还汇集了化学和生命科学领域的主要研究人员。2)细菌细胞分裂。与细胞壁组装蛋白紧密相连的是一系列辅助蛋白，它们提供时间相互作用、力产生和调节能力，以及细菌细胞分裂所必需的PBPs的底物相互作用。3)抗菌药物的发现。确定潜在的新型抗微生物作用是对抗抗生素耐药性增加的关键因素。沃里克参与了各种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，特别是高通量测序技术，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有能力将他们的经验转化为对抗微生物药物耐药性在卫生保健机构传播的理解。5)公共卫生流行病学。了解公共卫生对于更广泛地了解如何将新的科学发现转化为实际的健康效益至关重要。数学、生命科学和医学都是这一领域的强项。反过来，这些学科领域得到了华威大学在数学建模（人口和系统生物学）、成像技术和诊断方面公认的专业知识的支持。该提案有三个主要机制，通过这些机制，将弥合这些主题领域之间的差距，并发起富有成效的跨学科合作。1)短期学科跳跃奖学金。利用华威高等研究院开发的非常成功和具有成本效益的奖学金模式，我们将招聘初级博士后研究人员担任跨部门职位。2)集中的跨学科会议。这样的会议将采取多种形式，但将形成华威大学学术界、工业界和公共卫生研究人员以及其他机构学者之间的自然界面。我们打算举办度假学校、解决问题的讲习班和学习小组，以及更大的研究专题讨论会。潜在的早期会议可能侧重于“细胞膜穿越”、“细菌细胞分裂”和“医疗环境中的抗菌素耐药性”。3)访问奖学金。虽然我们相信华威大学在其所支持的技能广度方面是独一无二的，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，我们将邀请一些资深学者进行短期（3-6个月）访问研究。4)泵启动。这将向华威大学的所有研究人员开放，并将用于提高华威大学在抗菌素耐药性方面进行世界级、创新和令人兴奋的研究的能力。

项目成果

Communication Breakdown: Dissecting the COM Interfaces between the Subunits of Nonribosomal Peptide Synthetases

• DOI: 10.1021/acscatal.1c02113
• 发表时间: 2021-08-16
• 期刊: ACS CATALYSIS
• 影响因子: 12.9
• 作者: Fage, Christopher D.;Kosol, Simone;Lewandowski, Jozef R.
• 通讯作者: Lewandowski, Jozef R.

Inhibition of D-Ala:D-Ala ligase through a phosphorylated form of the antibiotic D-cycloserine.

• DOI: 10.1038/s41467-017-02118-7
• 发表时间: 2017-12-05
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Batson S;de Chiara C;Majce V;Lloyd AJ;Gobec S;Rea D;Fülöp V;Thoroughgood CW;Simmons KJ;Dowson CG;Fishwick CWG;de Carvalho LPS;Roper DI
• 通讯作者: Roper DI

'Something in the way she moves': The functional significance of flexibility in the multiple roles of protein disulfide isomerase (PDI).

• DOI: 10.1016/j.bbapap.2017.08.014
• 发表时间: 2017-11
• 期刊: Biochimica et biophysica acta. Proteins and proteomics
• 作者: Freedman RB;Desmond JL;Byrne LJ;Heal JW;Howard MJ;Sanghera N;Walker KL;Wallis AK;Wells SA;Williamson RA;Römer RA
• 通讯作者: Römer RA