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.

背景壁磷壁酸（WTA）是革兰氏阳性菌表面的糖复合物，在细胞生长、分裂和生物膜形成等过程中发挥重要作用。WTA结构在生物体中各不相同，但它们都含有甘油或核糖醇磷酸聚合物的共同核心。由于WTA是必不可少的发病机制，其生物合成已被提出作为一个潜在的目标抗菌剂。我们假设核糖醇-磷酸的修饰衍生物可以被开发为选择性和强大的WTA靶向工具，既作为成像探针，也作为WTA生物合成的靶向抑制剂或调节剂。利用化学修饰的核糖醇-磷酸衍生物开发一种新的WTA成像平台.合成新型核糖醇磷酸酯类似物作为WTA生物合成的选择性调节剂.使用上面开发的工具，以获得基本的见解，如何干扰WTA途径中的特定步骤对WTA的组成和分布的影响。新颖性该项目解决了目前缺乏针对核糖醇磷酸依赖性细胞过程的工具。它还提供了一个新的基于细胞的平台来成像WTA和特定的抑制剂。及时性抗生素耐药性是一个主要的和日益普遍的全球健康问题，强调了迫切需要确定新的治疗策略以及强大的技术来验证其有效性。实验方法跨学科的方法将强大的化学工具与先进的荧光显微镜技术相结合。将合成标记的核糖醇-磷酸衍生物，然后将其喂入相关的革兰氏阳性菌（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结构与报告分子缀合，使得能够通过超分辨率和衍射限制的荧光显微镜成像WTA的时空动力学。其他核糖醇磷酸衍生物将被开发为WTA生物合成途径中特定酶的抑制剂，并将使用新的成像平台进行表征。