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The cell wall of Gram-positive bacteria consists of an intricate network of proteins, peptidoglycan, and secondary cell wall structures (SCWS) that are covalently linked to the peptidoglycan. Teichoic or teichuronic acids are typical and well-studied SCWS in Gram-positive bacteria and play an important role in normal cell function and infection. Interestingly, many β-hemolytic streptococcal species appear to lack expression of typical teichoic or teichuronic acid structures and instead express a rhamnose-rich polysaccharide, which comprises approximately half of the cell wall by weight. Historically, expression of these evolutionary conserved glycans underlies classification of β-hemolytic streptococci in Lancefield groups (A, B, C, G...), a feature that is still made use of and applied in contemporary rapid test kits to diagnose and classify streptococcal infections.
The current research focus from the HD laboratory is on the biosynthesis pathway of the Group A Carbohydrate. In order to reveal details into the biosynthesis of this Streptococcus pyogenes virulence factor, we are applying a range of disciplines ranging from molecular biology, synthetic biology, biochemistry, mass-spectrometry and structural biology.
This research is conducted in collaboration with:
- Prof Brendan Wren, London School of Hygiene and Tropical Medicine, UK
- Prof Göran Widmalm, Stockholm University, Sweden
- Prof Jeroen Codee at the University of Leiden, The Netherlands
- Prof Nina van Sorge, Amsterdam UMC, The Netherland
- Prof Nicola Stanley-Wall, School of Life Sciences, Dundee, UK
- Arends DW, Miellet WR, Langereis JD, Ederveen THA, van der Gaast-de Jongh CE, van Scherpenzeel M, Knol MJ, van Sorge NM, Lefeber DJ, Trzciński K, Sanders EAM, Dorfmueller HC, Bootsma HJ, de Jonge MI. 2021. Examining the distribution and impact of single nucleotide polymorphisms in the capsular locus of Streptococcus pneumoniae serotype 19A. Infection and Immunity. 89(11):Article e00246-21. https://doi.org/10.1128/IAI.00246-21
Castro SA, Dorfmueller HC. 2021. A brief review on Group A Streptococcus pathogenesis and vaccine development. Royal Society Open Science. 8(3):Article 201991. https://doi.org/10.1098/rsos.201991
King H, Ajay Castro S, Pohane AA, Scholte CM, Fischetti VA, Korotkova N, Nelson DC, Dorfmueller HC. 2021. Molecular basis for recognition of the Group A Carbohydrate backbone by the PlyC streptococcal bacteriophage endolysin. Biochemical Journal. 478(12):2385-2397. https://doi.org/10.1042/BCJ20210158
Wagstaff BA, Zorzoli A, Dorfmueller HC. 2021. NDP-rhamnose biosynthesis and rhamnosyltransferases: building diverse glycoconjugates in nature. Biochemical Journal. 478(4):685-701. https://doi.org/10.1042/BCJ20200505
Zamakhaeva S, Chaton CT, Rush JS, Ajay Castro S, Kenner CW, Yarawsky AE, Herr AB, van Sorge NM, Dorfmueller HC, Frolenkov GI, Korotkov KV, Korotkova N. 2021. Modification of cell wall polysaccharide guides cell division in Streptococcus mutans. Nature Chemical Biology. 17:878-887. https://doi.org/10.1038/s41589-021-00803-9
Lenardon MD, Sood P, Dorfmueller H, Brown AJP, Gow NAR. 2020. Scalar nanostructure of the Candida albicans cell wall; a molecular, cellular and ultrastructural analysis and interpretation. Cell Surface. Publication
Zorzoli A, Meyer BH, Adair E, Torgov VI, Veselovsky VV, Danilov LL, Uhrin D, Dorfmueller HC*. Group A, B, C, and G Streptococcus Lancefield antigen biosynthesis is initiated by a conserved α-D-GlcNAc-β-1,4-L-rhamnosyltransferas. J Biol Chem. 2019 Sept 10. pii: jbc.RA119.009894. doi: 10.1074/jbc.RA119.009894
Wagstaff BA, Rejzek M, Kuhaudomlarp S, Hill L, Mascia I, Nepogodiev SA, Dorfmueller HC, Field RA*. Discovery of an RmlC/D fusion protein in the microalga Prymnesium parvum and its implications for NDP-β-L-rhamnose biosynthesis in microalgae. J Biol Chem. 2019 Apr 22. pii: jbc.RA118.006440. doi: 10.1074/jbc.RA118.006440.
van der Beek SL, Zorzoli A, Çanak E, Chapman RN, Lucas K, Meyer BH, Evangelopoulos D, de Carvalho LPS, Boons GJ, Dorfmueller HC*, van Sorge NM*. Streptococcal dTDP-L-rhamnose biosynthesis enzymes: functional characterization and lead compound identification. Mol Microbiol. 2019 Apr;111(4):951-964. doi: 10.1111/mmi.14197.
van der Beek SL, Le Breton Y, Ferenbach AT, Chapman RN, van Aalten DM, Navratilova I, Boons GJ, McIver KS, van Sorge NM*, Dorfmueller HC*. GacA is essential for Group A Streptococcus and defines a new class of monomeric dTDP-4-dehydrorhamnose reductases (RmlD). Mol Microbiol. 2015 Dec;98(5):946-62. doi: 10.1111/mmi.13169.
We have a bumper crop of promotions this year as part of the 2022 Annual Review process for academic staff.
Helge Dorfmueller has been awarded a Career Development Award from the Wellcome Trust.
In recent weeks staff who teach on Biological and Biomedical Sciences programmes have been recognised in the DUSA Student-led teaching awards and the BBSE awards.
Investigation of streptococcal cell wall biogenesis and glycoconjugate vaccine development
|Major Personal Funding Awards / Wellcome Career Development Award||2022|
|Major Personal Funding Awards / Wellcome Innovator Award||2020|
|PiCLS Best Mentor Award||2019|
|Major Personal Funding Awards / Tenovus Scotland Large Research Grant||2017|
|National Sciences Prizes awarded since 1990 / Tenovus Scotland Robin McLellan Award||2017|
|Personal Fellowships / Royal Society and Wellcome Trust Sir Henry Dale Fellowship||2016|
|Personal Fellowships / FEBS Short Term Fellowship to visit UMC Utrecht, The Netherlands||2015|
|Wellcome Trust Postdoctoral Training Fellowships||2010|