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

糖是地球上含量最丰富的生物分子，在能量储存、细胞识别和免疫反应等众多生物过程中发挥着重要作用。普遍存在的“唾液酸”糖Neu5Ac存在于所有人类细胞的表面，因此得到了很好的研究，但它的“邪恶孪生”伪氨基酸(PSE)存在于一系列细菌中，相比之下，人们对它知之甚少。PSE在包括多重耐药铜绿假单胞菌和鲍曼不动杆菌，以及胃部致病菌空肠弯曲菌和幽门螺杆菌在内的许多细菌种的表面上高度流行，现在越来越清楚的是，PSE的呈现和编辑对毒力至关重要。但是，尽管它是在30多年前发现的，我们对细菌如何以及为什么选择用这种糖来装饰它们的表面的确切了解还处于初级阶段。这主要是因为PSE非常复杂，因此对合成和研究具有挑战性。因此，在ChemGlycoSEPSIS中，我们将开发一种史无前例的化学糖生物学工具包，该工具包将提供基于PSE的酶底物、探针和抑制剂，以便能够剖析细菌的“Pseome”-并在此过程中建立PSE化学酶学领域。在三个跨学科的工作包中，我们将揭示PSE多糖是如何被细菌处理以及它们如何与宿主细胞相互作用的。具体来说，我们将集中在WPA：“PSE编写器”的剖析、发现和抑制；WPB：“PSE橡皮”的剖析、发现和抑制；以及WPC：与“PseReaders”结合的探索和抑制。到目前为止，这些生物学过程都没有明确的特征，因此我们不仅将提供对多糖加工的变革性分子水平的洞察，而且还将提供用于治疗感染的新型细胞探针和治疗线索。

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.