Structural studies of pilus biogenesis and bacterial adhesion

P菌毛和1型菌毛是尿路致病性大肠杆菌（UPEC）细菌的表面纤维，通过介导对宿主肾脏（P菌毛）和膀胱（1型菌毛）的附着，在细菌感染的发生中起重要作用。UPEC是尿路感染（uti）的主要病原体，在美国或欧洲，每年约有800万医生就诊和10万住院病例。事实上，据估计，每2名妇女中就有1名在其一生中感染尿路感染，其中20-40%将经历一次或多次复发感染。P型和1型菌毛的组装机制也在许多其他细菌病原体的表面细胞器的生物发生中起作用，包括潜在的生物恐怖剂鼠疫耶尔森菌。我们的研究计划集中在两个基本目标上：一是了解菌毛是如何在细菌表面组装的，二是发现新的抗生素，这将专门针对菌毛的组装。菌毛的组装需要两种特殊的蛋白质：一种是携带每个菌毛亚基并将它们运送到组装位点的伴侣蛋白，另一种是称为？引座员吗?作为装配平台和装配现场。过去，我们在理解伴侣如何工作方面取得了重大进展。因此，我们将把研究重点放在引座员身上。事实上，对于这种膜蛋白如何进行亚基的选择，它们如何按照确定的顺序组装以及它们如何通过膜分泌，我们所知甚少。本研究的另一个目标是发现能够抑制菌毛生物发生的新型抗生素。这种抗生素将非常有用，因为它们只会解除细菌病原体的武装，而不是像目前可用的抗生素那样杀死所有细菌（肠道菌群包括有益细菌）。以毒力因子为靶点的另一个好处是，产生耐药性的选择压力被认为大大降低了。我们研究的这两个目标将对公众健康产生相当大的影响。我们期望这项研究不仅能揭示导致疾病的过程，还将有助于了解通过细胞膜的分泌是如何进行的，这是一个发生在所有生命领域的生物过程。

P and type 1 pili are surface fibers of uropathogenic Escherichia coli (UPEC) bacteria that play essential roles in the onset of bacterial infection by mediating attachment to the host kidney (P pili) and bladder (type 1 pili). UPEC are the primary causative agents of urinary tract infections (UTIs), which account for an estimated 8 millions physician-office visits and 100,000 hospital admissions every year in the US or in Europe. Indeed, it has been estimated that 1 in 2 women will contract a UTI during their lives, and that 20-40% of these will experience one or more recurrent infections. P and type 1 pili are assembled by a mechanism that also functions in the biogenesis of surface organelles in many other bacterial pathogens, including the potential bioterrorism agent Yersinia pestis.Our research programme focuses on two essential goals: i- understanding how pili are assembled at the surface of the bacterium, and ii- discovering novel antibiotics, which will specifically target the assembly of pili.Assembly of pili requires two specialist proteins: a chaperone that takes up each pilus subunit and ferries them to a site of assembly, and a membrane pore protein termed ?the usher? that serves as assembly platform and site of assembly. In the past we have made significant progress in understanding how the chaperone works. We will therefore focus our research on the usher. Indeed very little is know as to how this membrane protein carries out selection of the subunits, their assembly in a defined order and their secretion through the membrane.Another goal of this research is the discovery of novel antibiotics able to inhibit pilus biogenesis. Such antibiotics would be very useful as they will disarm the bacterial pathogen only, instead of killing all bacteria (the gut flora includes beneficial bacteria) as is the case for the antibiotics presently available. The added advantage of targeting virulence factors is that the selective pressure for development of resistance is thought to be considerably lowered.These two goals of our research will have considerable impact on public health. We expect that the research will not only shed light on the processes that lead to disease but also will help understand how secretion through cell membranes, a biological process occurring in all realms of life, is carried out.