Primary Supervisor: Professor Paula Mendes, School of Chemical Engineering
Secondary supervisor: Professor Robin May
PhD project title: Development of synthetic glycan affinity reagents to study the capsular structure of fungal pathogens
University of Registration: University of Birmingham
Many pathogenic microorganisms produce extracellular polysaccharides that are attached to the cellular surface and are known as capsular polysaccharides. The capsules are a major virulence factor that act by protecting the microorganisms against host immune response and other antimicrobial agents. Among fungal pathogens, the opportunistic speciesCryptococcus neoformans is unique in having a large, complex capsule that is responsible for its ability to cause severe infections in humans. Cryptococcus is an emerging global health threat, responsible for more than 200 000 annual deaths worldwide. Current antifungal-based therapies have limited efficacy in eliminating the fungus. Thus, novel therapeutic strategies are greatly needed, but it depends on significant advances in understanding the biology and pathogenesis of Cryptococcus.
The capsule of Cryptococcus play a key role in modulating the intricate interactions between the fungus and the host, but the precise interactions that can either contribute to or prevent pathogenesis are currently unknown. Many fundamental aspects about the capsule structure-function relationship remain poorly understood, due to the lack of tools to study its complex polysaccharide chemical composition, organization and architecture. Lectins and anti-glycan antibodies are currently the main tools to recognise polysaccharides and provide information about the capsule chemical properties. However, they either lack specificity or are limited on the saccharide chains that they can recognise. Thus, there is the need to develop better tools to specifically recognise a broad spectrum of saccharide chains to significantly improve our knowledge about the structure and function of Cryptococcus capsules.
It is the goal of this interdisciplinary proposed research project to develop such saccharide recognition tools and provide unprecedented and comprehensive insights into the composition, organization and architecture of the Cryptococcuscapsule. This project will develop a modular synthetic approach, which involves concepts of molecular recognition, molecular assembly, multivalency and dynamic combinatorial chemistry, to generate peptide based-affinity reagents with exquisite specificity and high affinity for distinct saccharide chains. Fluorescent tags will be chemically conjugated to the peptide based-affinity reagents for facilitating imaging studies. The novel glycan affinity reagents will be subsequently employed to create a high-resolution chemical mapping of the Cryptococcus capsule.
- Corbett, P. T.; Leclaire, J.; Vial, L.; West, K. R.; Wietor, J. L.; Sanders, J. K. M.; Otto, S., Dynamic combinatorial chemistry. Chem. Rev. 2006, 106 (9), 3652-3711.
- Wang ZA, Li LX, Doering TL. Unraveling synthesis of the cryptococcal cell wall and capsule. Glycobiology. 2018 Oct 1;28(10):719-730. doi: 10.1093/glycob/cwy030.
BBSRC Strategic Research Priority: Understanding the Rules of Life: Microbiology
Techniques that will be undertaken during the project:
- Peptide synthesis
- Dynamic combinatorial chemistry
- High performance liquid chromatography
- Isothermal titration calorimetry
- Live and fixed cell microscopy
- Super-resolution imaging
- Flow cytometry
Contact: Professor Paula Mendes, University of Birmingham