Bacterial cell wall architecture

细菌细胞壁结构

• 批准号: BB/L006162/1
• 负责人: Simon J. Foster
• 金额: $ 86.23万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL006162%2F1
• 关键词: Bacterial; cell; wall; architecture

The bacterial cell wall is essential for viability, shape determination and its production is the target of the most important types of antibiotics ever discovered (such as penicillin). The alarming spread of antibiotic resistance means it is crucial to understand more about this structure if we are to define new potential ways to control bacterial disease. The cell wall is like an exoskeleton (called the sacculus) that is able to withstand the considerable internal forces that would otherwise rupture the cell. The major structural element of the cell wall for most bacteria is a polymer called peptidoglycan (PG), which is unique to bacteria. PG is a single large, bag-like molecule that surrounds the cell and whilst very strong is also dynamic to allow the cells to grow and divide. Even though PG is chemically only made of relatively simple building blocks how these are assembled to produce an architecture able to fulfil the many functions of PG has remained largely elusive. The problem is that architecture has to be viewed in situ and bacteria are on the micron scale. To address this problem, in the last few years we have taken an interdisciplinary approach using a combination of biochemistry and high-resolution microscopy techniques. The new information gained has completely altered our views on PG architecture overturning previous models and revealing a hitherto unexpected complexity. We have now applied our approach to many different organisms and have discovered several different architectures from rings and knobbles in the human pathogen Staphylococcus aureus to cables in the rod shaped bacterium Bacillus subtilis and a heterogeneous architecture of pores and thicker regions in organisms such as Escherichia coli. In order to explain how such PG features allow the bacteria to maintaining cell integrity and yet be dynamic we have proposed new models for growth and division for several important bacterial species. To map sites of new PG synthesis we have a super-resolution fluorescence microscope and a totally new and unique machine capable of correlating different forms of microscopy. We are now ready to take the next step to actually solve the architecture of PG at the chemical level. This will give great insights into the fundamental biology of bacteria, how they are able to grow and divide and the action of important antibiotics. Amazingly, we know the target of penicillin but not how it kills bacteria. New understanding will require not only the development and use of ultra-resolution microscopy approaches, but also the synthesis of a suite of chemical probes such that we will be able to "see chemistry". Several of the proposed microscopy approaches have not been applied to biological samples before and so we will pave the way for their wider application.

细菌细胞壁对于生存能力，确定形状及其产生是有史以来最重要的抗生素类型（例如青霉素）的目标。抗生素耐药性的惊人传播意味着，如果我们要定义控制细菌疾病的新潜在方法，那么了解这种结构至关重要。细胞壁就像一个外骨骼（称为囊），能够承受否则会破裂细胞的大量内部力。大多数细菌的细胞壁的主要结构元素是一种称为肽聚糖（PG）的聚合物，它是细菌所特有的。 PG是一个单个大型袋状分子，围绕细胞，虽然非常强，但也具有动态性，可以使细胞生长和分裂。即使PG在化学上仅由相对简单的构件制成，它们如何组装它们以生成能够实现PG的许多功能的体系结构，这在很大程度上仍然难以捉摸。问题在于必须原位观察建筑，并且细菌处于微米尺度上。为了解决这个问题，在过去的几年中，我们使用生物化学和高分辨率显微镜技术的组合采取了跨学科的方法。获得的新信息完全改变了我们对PG体系结构推翻以前模型的看法，并揭示了迄今为止意外的复杂性。现在，我们已经将方法应用于许多不同的生物体，并发现了金黄色葡萄球菌中的环和旋钮的几种不同的建筑，到杆状细菌枯草杆菌的电缆以及诸如Escherichia Coli等生物体中的孔和厚区域的异质结构。为了解释这样的PG特征如何使细菌保持细胞完整性，但是动态的，我们提出了一些新的模型，用于几种重要的细菌物种的生长和分裂。为了绘制新PG合成的位点，我们具有超分辨率的荧光显微镜和一个全新的独特机器，能够将不同形式的显微镜相关联。现在，我们准备迈出下一步，实际解决PG在化学水平上的结构。这将为细菌的基本生物学，它们如何成长和分裂以及重要抗生素的作用提供深刻的见解。令人惊讶的是，我们知道青霉素的靶标，但不知道它如何杀死细菌。新的理解不仅需要开发和使用超分辨率显微镜方法，而且还需要一组化学探针的合成，以便我们能够“看化学”。以前，提出的几种显微镜方法尚未应用于生物样品，因此我们将为其更广泛的应用铺平道路。

项目成果

ELM: super-resolution analysis of wide-field images of fluorescent shell structures.

ELM：荧光壳结构的宽视场图像的超分辨率分析。

• DOI: 10.1088/2050-6120/aac28e
• 发表时间: 2018
• 期刊: Methods and applications in fluorescence
• 影响因子: 3.2
• 作者: Manton JD

Molecular imaging of glycan chains couples cell-wall polysaccharide architecture to bacterial cell morphology.

• DOI: 10.1038/s41467-018-03551-y
• 发表时间: 2018-03-28
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Turner RD;Mesnage S;Hobbs JK;Foster SJ
• 通讯作者: Foster SJ

Molecular coordination of Staphylococcus aureus cell division.

• DOI: 10.7554/elife.32057
• 发表时间: 2018-02-21
• 期刊: eLife
• 影响因子: 7.7
• 作者: Lund VA;Wacnik K;Turner RD;Cotterell BE;Walther CG;Fenn SJ;Grein F;Wollman AJ;Leake MC;Olivier N;Cadby A;Mesnage S;Jones S;Foster SJ
• 通讯作者: Foster SJ

Bactericidal activity of the human skin fatty acid cis-6-hexadecanoic acid on Staphylococcus aureus.

• DOI: 10.1128/aac.01043-13
• 发表时间: 2014-07
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Cartron ML;England SR;Chiriac AI;Josten M;Turner R;Rauter Y;Hurd A;Sahl HG;Jones S;Foster SJ
• 通讯作者: Foster SJ

Staphylococcus aureus cell wall structure and dynamics during host-pathogen interaction.

• DOI: 10.1371/journal.ppat.1009468
• 发表时间: 2021-03
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Sutton JAF;Carnell OT;Lafage L;Gray J;Biboy J;Gibson JF;Pollitt EJG;Tazoll SC;Turnbull W;Hajdamowicz NH;Salamaga B;Pidwill GR;Condliffe AM;Renshaw SA;Vollmer W;Foster SJ
• 通讯作者: Foster SJ