Probing and manipulating the bacterial cell wall using chemically modified sugars
Lead Research Organisation:
University of York
Department Name: Chemistry
Abstract
Background
Wall 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.
Objectives
1. 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.
Novelty
The 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.
Timeliness
Antimicrobial 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 approach
The 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.
Wall 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.
Objectives
1. 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.
Novelty
The 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.
Timeliness
Antimicrobial 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 approach
The 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.
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/T007222/1 | 01/10/2020 | 30/09/2028 | |||
| 2885428 | Studentship | BB/T007222/1 | 01/10/2023 | 30/09/2027 |