ChemGlycoSEPSIS - Chemical glycobiology for the study and exploitation of pseudaminic acid sugars in infectious diseases

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Sugars, or glycans as they are commonly known, are the most abundant biomolecule on earth and play essential roles in a myriad ofbiological processes including energy storage, cell-cell recognition and the immunological response. The ubiquitous 'sialic acid' sugarNeu5Ac is present on the surface of all human cells and is therefore well studied, but its 'evil twin' pseudaminic acid (Pse), which ispresent in a range of bacteria, is poorly understood in comparison. Pse is highly prevalent on the surface of a number of bacterialspecies including multidrug resistant ESKAPE pathogens P. aeruginosa and A. baumannii, and gastric pathogens C. jejuni and H.pylori, and it is now increasingly clear that Pse presentation and editing is important for virulence. But despite its discovery over thirtyyears ago our understanding of exactly how and why bacteria choose to decorate their surfaces with this sugar is in its infancy. This isprimarily because Pse is fiendishly complex and therefore challenging to synthesise and study. In ChemGlycoSEPSIS will we thereforedevelop an unprecedented chemical glycobiology toolkit which will deliver Pse based enzyme substrates, probes and inhibitors toenable dissection of the bacterial 'Pseome'- and in the process establish the field of Pse chemical enzymology. Across threetransdisciplinary work-packages, we will unpick how Pse glycans are processed by bacteria and how they interact with host cells.Specifically we will focus on WPA: the dissection, discovery and inhibition of 'Pse Writers' ; WPB: the dissection,discovery and inhibition of 'Pse Erasers'; and WPC: the exploration and inhibition of binding to 'PseReaders' . To date none of these biological processes have been unequivocally characterised so we will not only delivertransformational molecular level insight into glycan processing but also novel cellular probes and therapeutic leads for treatinginfections.