Structural studies of pilus biogenesis and bacterial adhesion

菌毛生物发生和细菌粘附的结构研究

• 批准号: G0800002/1
• 负责人: Gabriel Waksman
• 金额: $ 158.57万
• 依托单位: Birkbeck, University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0800002%2F1
• 关键词: Structural; studies; pilus; biogenesis; bacterial

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.

P 菌毛和 1 型菌毛是泌尿道致病性大肠杆菌 (UPEC) 细菌的表面纤维，通过介导与宿主肾脏 (P 菌毛) 和膀胱 (1 型菌毛) 的附着，在细菌感染的发生中发挥重要作用。 UPEC 是尿路感染 (UTI) 的主要病原体，在美国或欧洲，每年约有 800 万人次就诊，10 万人次住院。事实上，据估计，有二分之一的女性一生中会感染尿路感染，其中 20-40% 会经历一种或多种反复感染。 P 型菌毛和 1 型菌毛的组装机制在许多其他细菌病原体的表面细胞器的生物合成中也发挥作用，包括潜在的生物恐怖剂鼠疫耶尔森氏菌。我们的研究计划重点关注两个基本目标：i-了解菌毛如何在细菌表面组装，ii-发现专门针对菌毛组装的新型抗生素。菌毛的组装需要两名专家 蛋白质：一种分子伴侣，它占据每个菌毛亚基并将它们运送到组装位点，以及一种膜孔蛋白，称为“引导者”。作为装配平台和装配地点。过去，我们在理解伴侣的工作原理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，人们对这种膜蛋白如何选择亚基、如何按确定的顺序组装以及如何通过膜分泌知之甚少。这项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）。针对毒力因子的额外优势是，耐药性发展的选择压力被认为大大降低。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够揭示导致疾病的过程，而且有助于了解细胞膜分泌这一发生在生命各个领域的生物过程是如何进行的。