Structural and molecular investigations of membrane-embedded pilus assembly nanomachines in Gram-negative bacterial pathogens

革兰氏阴性细菌病原体中膜嵌入菌毛组装纳米机器的结构和分子研究

• 批准号: MR/K018434/1
• 负责人: Gabriel Waksman
• 金额: $ 215.06万
• 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: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK018434%2F1
• 关键词: Structural; molecular; investigations; membrane; embedded

Bacterial pili are cell surface appendages produced by bacterial pathogens. Pili are used by bacteria for recognition of and attachment to host tissues. Once attached to the host, the bacterium can start the process of infection. Therefore, pili are important means by which a pathogenic bacterium infects a host. Pili are large polymers of protein subunits termed pilins. Polymerisation of pilins into a mature pilus is mediated and orchestrated by macromolecular complexes embedded in the bacterial cell envelope. These complexes are large and often composed of many proteins. They function like machines and catalysts, grabbing individual pilins, catalysing their polymerisation, and facilitating their secretion through the bacterial envelope and their exposure at the bacterial cell surface. The major objective of this proposal is to investigate the structure and function of these machines, to understand how they work, and also, eventually, to find ways to inhibit them. Inhibiting the production of pili by bacteria would be very advantageous: i- without pili, the pathogenic bacterium cannot attach to its target tissue, and is therefore harmless; ii- because selective inhibition of pilus production is non-lethal, all the "good" bacteria which we naturally harbour in our bodies (the microbiome) and which play very beneficial roles will survive treatment. The concept of only inhibiting the pathogen while protecting the "good" bacteria from antibiotics action is a new concept in antimicrobials design, a concept that holds enormous promise for combating infectious diseases caused by bacteria. We are in a unique position to achieve these goals. Our track record is unique in the field of bacterial pathogenesis in general and pilus biogenesis in particular. Our structural biology work can be directly used to design small molecules capable of binding and disrupting crucial steps in the process of generating pili and secreting them.

细菌毛是由细菌病原体产生的细胞表面附属物。菌毛被细菌用来识别和附着宿主组织。一旦附着在宿主上，细菌就可以启动感染过程。因此，菌毛是病原菌感染宿主的重要途径。菌毛是一种蛋白质亚单位的大聚合物，称为菌毛蛋白。菌毛蛋白聚合成成熟菌毛是由嵌入细菌细胞膜的大分子复合体介导和协调的。这些复合体很大，通常由许多蛋白质组成。它们的功能就像机器和催化剂，抓住单个菌毛蛋白，催化它们的聚合，并促进它们通过细菌包膜分泌和暴露在细菌细胞表面。这项提案的主要目标是调查这些机器的结构和功能，了解它们是如何工作的，并最终找到抑制它们的方法。抑制细菌产生菌毛将是非常有利的：一--没有菌毛，病原菌不能附着在其目标组织上，因此是无害的；二--因为选择性地抑制菌毛的生产是非致命性的，我们体内自然藏匿的所有“好”细菌(微生物组)都将在治疗中存活下来。只抑制病原体，同时保护“好”细菌免受抗生素作用的概念是抗菌素设计中的一个新概念，这一概念在抗击细菌引起的传染病方面有着巨大的希望。我们处于实现这些目标的独特地位。我们在细菌致病，特别是菌毛生物发生方面的记录是独一无二的。我们的结构生物学工作可以直接用于设计能够结合和破坏菌毛生成和分泌过程中的关键步骤的小分子。

项目成果

Structural and energetic basis of folded-protein transport by the FimD usher.

• DOI: 10.1038/nature12007
• 发表时间: 2013-04-11
• 期刊: Nature
• 影响因子: 64.8

Dissection of pilus tip assembly by the FimD usher monomer.

• DOI: 10.1016/j.jmb.2012.12.024
• 发表时间: 2013-03-11
• 期刊: JOURNAL OF MOLECULAR BIOLOGY
• 影响因子: 5.6
• 作者: Allen, William J.;Phan, Gilles;Hultgren, Scott J.;Waksman, Gabriel
• 通讯作者: Waksman, Gabriel

The Cryoelectron Microscopy Structure of the Type 1 Chaperone-Usher Pilus Rod.

• DOI: 10.1016/j.str.2017.10.004
• 发表时间: 2017-12-05
• 期刊: Structure (London, England : 1993)
• 作者: Hospenthal MK;Zyla D;Costa TRD;Redzej A;Giese C;Lillington J;Glockshuber R;Waksman G
• 通讯作者: Waksman G

Ordered and ushered; the assembly and translocation of the adhesive type I and p pili.

• DOI: 10.3390/biology2030841
• 发表时间: 2013-06-26
• 期刊: Biology
• 影响因子: 4.2
• 作者: Lillington J;Waksman G
• 通讯作者: Waksman G