Probing and manipulating the bacterial cell wall using chemically modified sugars

使用化学修饰糖探测和操纵细菌细胞壁

• 批准号: 2885428
• 金额: --
• 依托单位: University of York
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2885428
• 关键词: Probing; manipulating; bacterial; cell; wall

BackgroundWall teichoic acids (WTAs) are glycoconjugates on the surface of gram-positive bacteria that play important roles in, for example, cell growth, division and biofilm formation. WTA structures vary among organisms but they all contain common cores of glycerol- or ribitol-phosphate polymers. Since WTAs are essential for pathogenesis, their biosynthesis has been proposed as a potential target for antibacterial agents. We hypothesise that modified derivatives of ribitol-phosphate can be developed as selective and powerful WTA-targeting tools, both as imaging probes and as targeted inhibitors or modulators of WTA biosynthesis.Objectives1. To develop a new imaging platform for WTAs using chemically modified ribitol-phosphate derivatives.2. To synthesise novel ribitol-phosphate analogues as selective modulators of WTA biosynthesis.3. To use the tools developed above to gain fundamental insights into how interfering with specific steps in the WTA pathway impacts on WTA composition and distribution.NoveltyThe project addresses a current lack of tools targeting ribitol-phosphate-depending cellular processes. It also delivers a new cell-based platform to image WTAs and characterise pathway-specific inhibitors.TimelinessAntimicrobial resistance is a major and increasingly prevalent global health concern, underscoring the urgent need for identification of new therapeutic strategies as well as robust technologies to characterise their effectiveness.Experimental approachThe interdisciplinary approach combines powerful chemical tools with advanced fluorescence microscopy techniques. Tagged ribitol-phosphate derivatives will be synthesised and then fed to relevant gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis) to be incorporated into WTAs. Conjugation of the resulting tagged WTA structure to a reporter molecule enables imaging of the spatial-temporal dynamics of WTA by super-resolution and diffraction-limited fluorescence microscopy. Additional ribitol-phosphate derivatives will be developed as inhibitors for specific enzymes in the WTA biosynthetic pathway and will be characterised using the new imaging platform.

背景壁te曲酸（WTA）是革兰氏阳性细菌表面上的糖缀合物，在例如细胞生长，分裂和生物膜形成中起着重要作用。 WTA结构在生物体之间各不相同，但它们都包含甘油或核糖醇 - 磷酸聚合物的常见核心。由于WTA对于发病机理至关重要，因此已提出它们的生物合成是抗菌剂的潜在靶标。我们假设核糖醇 - 磷酸的修饰衍生物可以作为选择性和强大的WTA靶向工具，无论是成像探针还是靶向抑制剂或WTA生物合成的靶向抑制剂或调节剂。使用化学修饰的核糖醇 - 磷酸衍生物为WTA开发新的成像平台2。将新型的核糖醇 - 磷酸类似物合成为WTA生物合成的选择性调节剂3。使用上面开发的工具来获得基本的见解，以了解WTA途径中特定步骤如何影响WTA组成和分布。Noveltythe The Project解决了目前缺乏针对核糖醇 - 磷酸细胞过程的工具。它还提供了一个新的基于细胞的平台来对WTA进行图像并表征特异性抑制剂。TimelinesilenceAntimicrobial耐药性是一个主要且日益普遍的全球健康问题，强调了迫切需要鉴定新的治疗策略，以识别新的治疗技术，以及具有有效性的技术互动工具。标记的核糖醇 - 磷酸衍生物将合成，然后将其喂入相关的革兰氏阳性细菌（金黄色葡萄球菌和枯草芽孢杆菌）以掺入WTA中。将所得标记的WTA结构与报告者分子的结合可以通过超分辨率和衍射限量荧光显微镜对WTA的时空动力学进行成像。其他核糖醇 - 磷酸衍生物将作为WTA生物合成途径中特定酶的抑制剂开发，并将使用新成像平台进行表征。