How do pathogenic Gram-negative bacteria successfully adhere to host surfaces under hydrodynamic flow, and which key targets in the adhesion process should new drugs aim for?

粘附性在细菌的生命周期中起着重要作用。通过特定的靶分子与宿主细胞建立第一次接触，黏附过程是细菌渗透的先决条件。一旦细菌进入宿主，它们就会开始定居，从而导致感染。粘附力本身是由粘附素分子介导的，对于革兰氏阴性细菌来说，粘附素分子可以在菌毛的最末端找到。这些线状的细胞外延伸建立了与宿主细胞的初始接触。然后，位于细菌表面的更多粘附素分子加强了这种结合。因此，对抗细菌感染的一个新假说是攻击和阻断病原菌的黏附能力，例如通过改变菌毛的生物力学性质。这是我提出的项目的主要目标。本研究的目的是研究抗体(单抗和多克隆抗体)、抗菌肽和化学制剂对革兰氏阴性菌黏附过程的影响。据信，这种物质会通过使菌毛的结构变得更坚硬，从而降低细菌的黏附能力，从而影响菌毛的生物力学性能。根据这一假设，我将使用光钳、平行平板流室、透射电子显微镜和计算机模拟来探索菌毛的特性，例如它们的灵活性。对革兰氏阴性菌与宿主细胞黏附的准确了解为未来制定抗细菌感染的策略提供了基础，特别是在耐药细菌数量不断增加的背景下。

Adhesion plays a major role in the life cycle of bacteria. By establishing the first contact to the host cell via specific target molecules, the adhesion process is the prerequisite for bacterial infiltration. Once the bacteria are in the host, they can start to colonize and thus cause an infection. The adhesion itself is mediated by adhesin molecules which, in case of Gram-negative bacteria, can be found e.g. at the very end of the pili. These thread-like extracellular extensions establish the initial contact with the host cell. Afterwards, the bond is strengthened by further adhesin molecules, located at the bacteria surface. Therefore, a new hypothesis to fight bacterial infections is to attack and block the adhesive abilities of pathogenic bacteria, e.g. by changing the biomechanical properties of the pili. This is the main objective of my proposed project. In detail, my aim is to investigate the adhesion process of Gram-negative bacteria under the influence of antibodies (monoclonal and polyclonal), antibacterial peptides and chemical agents. It is believed that such substances can affect the biomechanical properties of the pili shaft by making their structure stiffer, and thus reducing adhesion ability of bacteria. Following this hypothesis, I will probe the properties of pili, e.g. their flexibility, using optical tweezers, parallel-plate flow chambers, transmission electron microscopy and computer simulations. The precise knowledge of the adhesion of Gram-negative bacteria to host cells provide the basis for the future development of strategies of fight bacterial infections, particularly in the context of rising numbers of antibiotic-resistant germs.