Bacterial Cell Envelope Biogenesis

大多数细菌的大小为1/1000毫米，作为单细胞生物体繁殖，通常一代时间可以短至20分钟。细菌也非常强大，可以在一系列不同的环境中生存。虽然大多数细菌对人类或地球生态系统具有有利的作用，但有些细菌可能会导致严重的感染性疾病，需要通过抗菌药物进行治疗。然而，许多病原菌已经获得了抵抗抗生素的能力，这成为我们社会的主要负担，并使新抗生素的开发成为高度优先事项。特别成问题的是致病性革兰氏阴性细菌。革兰氏阴性菌的定义特征是它们的外膜，它本质上对许多抗生素是不可渗透的，因此对这些药物产生了天然的耐药性。外膜与细胞壁紧密相连，也称为肽聚糖，它保护细胞免受其内部渗透压的破裂。外膜和细胞壁都是基本的细胞包膜结构，化学物质或酶使它们不稳定，可使细菌细胞对抗生素敏感或导致细胞死亡。事实上，一些最好的抗生素，如青霉素或糖肽，直接作用于细胞壁的合成，最近发现的抗菌化合物很少抑制外膜的生物合成，生长和分裂的细菌通过合成细胞内的成分并将它们插入现有的层来扩大它们的细胞包膜。由于外膜包围着细胞壁，新合成的外膜成分必须通过细胞壁转运到外膜。细胞如何通过细胞壁运输外膜组分以及它如何协调外膜扩张与细胞壁生长以维持细胞包膜的稳定性尚不清楚。这个项目的主题是破译这种协调的分子机制。我们将使用分子生物学，生物化学和生物物理学方法来确定细胞壁如何影响外膜的生物发生，以及动态细胞包膜过程如何影响细胞壁结构。此外，我们还将研究外膜和细胞壁之间的紧密连接如何影响外膜生长的细胞包膜运输过程。我们希望该项目将揭示分子机制，增强我们对细菌细胞的基本知识，并可被新型抗菌药物靶向。

Most bacteria have a size of 1/1000 of a millimetre and propagate as single-cell organism, often with a generation time that can be as short as 20 minutes. Bacteria are also remarkably robust and can survive in a range of different environments. Whilst most bacteria have advantageous roles for humans or the earth's ecosystems, some can cause severe infectious diseases that need to be treated by antibacterial drugs. However, many pathogenic bacteria have acquired the ability to resist antibiotics which became a major burden to our society and makes the development of new antibiotics a high priority. Particularly problematic are pathogenic Gram-negative bacteria. The defining feature of Gram-negative bacteria is their outer membrane, which is intrinsically impermeable to many antibiotics and thus confers a natural resistance to these drugs.The outer membrane is tightly connected to the cell wall, also called peptidoglycan, which protects the cell from bursting by its internal osmotic pressure. Both, the outer membrane and the cell wall are essential cell envelope structures and their destabilization by chemicals or enzymes can render a bacterial cell susceptible to antibiotics or lead to cell death. Indeed, some of our best antibiotics, like penicillins or glycopepides, directly target the synthesis of the cell wall and few recently identified antibacterial compounds inhibit the biogenesis of the outer membrane.Growing and dividing bacteria enlarge their cell envelope by synthesizing its components inside the cell and inserting them into the existing layers. Because the outer membrane surrounds the cell wall, the newly synthesized outer membrane components must be transported through the cell wall to the outer membrane. How the cell transports the outer membrane components through the cell wall and how it coordinates outer membrane expansion with cell wall growth to maintain the stability of the cell envelope, is not known. The topic of this project is to decipher the molecular mechanisms of this coordination. We will use molecular biology, biochemical and biophysical methods to determine how the cell wall affects the biogenesis of the outer membrane, and how the dynamic cell envelope processes affect the cell wall structure. In addition, we will investigate how the tight connections between the outer membrane and cell wall affect the cell envelope transport processes for outer membrane growth. We expect that the project will unravel molecular mechanisms that enhance our fundamental knowledge of a bacterial cell and can be targeted by novel antibacterial drugs.