Bacterial cell wall architecture

细菌细胞壁对细菌的存活和形状确定是必不可少的，它的产生是迄今发现的最重要类型抗生素(如青霉素)的靶标。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的潜在方法，更多地了解这种结构是至关重要的。细胞壁就像一个外骨骼(称为球囊)，能够承受相当大的内力，否则细胞就会破裂。大多数细菌细胞壁的主要结构元素是一种称为肽聚糖(PG)的聚合物，这是细菌所独有的。PG是一个包裹在细胞周围的大的袋状分子，虽然非常强大，但也是动态的，允许细胞生长和分裂。尽管PG在化学上只是由相对简单的构建块组成，但如何组装这些构建块来产生能够实现PG的许多功能的体系结构，在很大程度上仍然难以捉摸。问题是，建筑必须在现场观察，细菌是微米级的。为了解决这个问题，在过去的几年里，我们采取了一种结合生物化学和高分辨率显微镜技术的跨学科方法。获得的新信息完全改变了我们对PG架构的看法，颠覆了以前的模型，揭示了迄今为止意想不到的复杂性。我们现在已经将我们的方法应用于许多不同的生物，并发现了几种不同的结构，从人类病原体金黄色葡萄球菌中的环和节，到杆状细菌枯草杆菌中的线缆，以及大肠杆菌等生物中由毛孔和较厚区域组成的异质结构。为了解释这种PG特征如何使细菌保持细胞完整性，同时又是动态的，我们为几个重要的细菌物种提出了新的生长和分裂模型。为了绘制新的PG合成的位置图，我们有一个超分辨率荧光显微镜和一台全新的独特的机器，能够关联不同形式的显微镜。我们现在准备好进入下一步，在化学层面上实际解决PG的架构。这将使人们对细菌的基本生物学、它们如何生长和分裂以及重要抗生素的作用有很大的了解。令人惊讶的是，我们知道青霉素的目标，但不知道它是如何杀死细菌的。新的理解不仅需要开发和使用超分辨率显微镜方法，还需要合成一套化学探针，以便我们能够“看到化学”。一些提出的显微镜方法以前没有被应用于生物样本，所以我们将为它们的更广泛的应用铺平道路。

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.