A sugar called pseudaminic acid sits on the surface of dangerous bacteria, yet scientists have struggled for thirty years to study it because it is so chemically difficult to make and handle. This project will build a new chemical toolkit—enzymes, probes, and inhibitors—to finally crack open how bacteria use this sugar to cause disease. Pseudaminic acid is the "evil twin" of a common human sugar, sialic acid, but it appears on multidrug-resistant pathogens like *P. aeruginosa* and *A. baumannii*, as well as stomach bugs *C. jejuni* and *H. pylori*. Researchers know the sugar is linked to virulence, but the precise molecular mechanisms—how bacteria write, erase, and read these sugar decorations—remain unknown. Without this understanding, designing drugs that target the sugar is guesswork. If successful, the project will deliver the first clear molecular picture of pseudaminic acid processing in bacteria. That could lead to entirely new classes of antibiotics that block the sugar’s role in infection, offering a route to treat drug-resistant infections that currently have few options. This is fundamental chemical biology: the immediate payoff is deep mechanistic knowledge, not a finished medicine. But past work on similar sugars has repeatedly opened unexpected therapeutic doors.
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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 of biological processes including energy storage, cell-cell recognition and the immunological response. The ubiquitous 'sialic acid' sugar Neu5Ac is present on the surface of all human cells and is therefore well studied, but its 'evil twin' pseudaminic acid (Pse), which is present in a range of bacteria, is poorly understood in comparison. Pse is highly prevalent on the surface of a number of bacterial species 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 thirty years ago our understanding of exactly how and why bacteria choose to decorate their surfaces with this sugar is in its infancy. This is primarily because Pse is fiendishly complex and therefore challenging to synthesise and study. In ChemGlycoSEPSIS will we therefore develop an unprecedented chemical glycobiology toolkit which will deliver Pse based enzyme substrates, probes and inhibitors to enable dissection of the bacterial 'Pseome'- and in the process establish the field of Pse chemical enzymology. Across three transdisciplinary 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 'Pse Readers' . To date none of these biological processes have been unequivocally characterised so we will not only deliver transformational molecular level insight into glycan processing but also novel cellular probes and therapeutic leads for treating infections.
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