Therapeutic Approaches Targeting the Assembly and Function of Chaperone-Usher Pili.

Q1 Medicine EcoSal Plus Pub Date : 2019-03-01 DOI:10.1128/ecosalplus.ESP-0033-2018
John J Psonis, David G Thanassi
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Abstract

The chaperone-usher (CU) pathway is a conserved secretion system dedicated to the assembly of a superfamily of virulence-associated surface structures by a wide range of Gram-negative bacteria. Pilus biogenesis by the CU pathway requires two specialized assembly components: a dedicated periplasmic chaperone and an integral outer membrane assembly and secretion platform termed the usher. The CU pathway assembles a variety of surface fibers, ranging from thin, flexible filaments to rigid, rod-like organelles. Pili typically act as adhesins and function as virulence factors that mediate contact with host cells and colonization of host tissues. Pilus-mediated adhesion is critical for early stages of infection, allowing bacteria to establish a foothold within the host. Pili are also involved in modulation of host cell signaling pathways, bacterial invasion into host cells, and biofilm formation. Pili are critical for initiating and sustaining infection and thus represent attractive targets for the development of antivirulence therapeutics. Such therapeutics offer a promising alternative to broad-spectrum antibiotics and provide a means to combat antibiotic resistance and treat infection while preserving the beneficial microbiota. A number of strategies have been taken to develop antipilus therapeutics, including vaccines against pilus proteins, competitive inhibitors of pilus-mediated adhesion, and small molecules that disrupt pilus biogenesis. Here we provide an overview of the function and assembly of CU pili and describe current efforts aimed at interfering with these critical virulence structures.

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针对伴侣纤毛虫组装和功能的治疗方法。
合子-usher(CU)途径是一种保守的分泌系统,专门用于组装多种革兰氏阴性细菌的超家族毒力相关表面结构。通过 CU 途径进行的脓疱生物生成需要两种特殊的组装元件:一种是专用的周质体伴侣蛋白,另一种是称为 "引导者 "的整体外膜组装和分泌平台。CU 途径可组装各种表面纤维,从纤细、柔韧的丝状物到坚硬、棒状的细胞器。纤毛通常作为粘附素和毒力因子发挥作用,介导与宿主细胞的接触和宿主组织的定殖。纤毛虫介导的粘附对感染的早期阶段至关重要,可使细菌在宿主体内立足。纤毛还参与宿主细胞信号通路的调节、细菌侵入宿主细胞以及生物膜的形成。纤毛对于启动和维持感染至关重要,因此是开发抗病毒疗法的诱人靶点。这种疗法有望替代广谱抗生素,并提供了一种在保护有益微生物群的同时对抗抗生素耐药性和治疗感染的方法。开发抗柔毛治疗药物的策略有很多,包括针对柔毛蛋白的疫苗、柔毛介导粘附的竞争性抑制剂以及破坏柔毛生物生成的小分子药物。在此,我们将概述中大纤毛虫纤毛的功能和组装,并介绍目前为干扰这些关键毒力结构所做的努力。
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来源期刊
EcoSal Plus
EcoSal Plus Immunology and Microbiology-Microbiology
CiteScore
12.20
自引率
0.00%
发文量
4
期刊介绍: EcoSal Plus is the authoritative online review journal that publishes an ever-growing body of expert reviews covering virtually all aspects of E. coli, Salmonella, and other members of the family Enterobacteriaceae and their use as model microbes for biological explorations. This journal is intended primarily for the research community as a comprehensive and continuously updated archive of the entire corpus of knowledge about the enteric bacterial cell. Thoughtful reviews focus on physiology, metabolism, genetics, pathogenesis, ecology, genomics, systems biology, and history E. coli and its relatives. These provide the integrated background needed for most microbiology investigations and are essential reading for research scientists. Articles contain links to E. coli K12 genes on the EcoCyc database site and are available as downloadable PDF files. Images and tables are downloadable to PowerPoint files.
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