BESPOKE – Bacterial Enzyme and Surface Polymer Exploration Kit

forthcoming

Antimicrobial resistance (AMR) is a major health challenge and predicted to be associated with 8-10 million deaths per year by 2050. Gram-positive pathogens from the genus Enteroccocus and Gram-negative extra-intestinal pathogenic Escherichia coli (ExPEC) are critical multidrug-resistant bacteria for which effective therapies are urgently needed. Both pathogens cause various types of infections, can survive in different biological niches, and can even be a beneficial part of the human gut microbiome. Glycoconjugate vaccines have proven highly effective for the prevention of bacterial infections. However, their development for Enterococcus spp. and ExPEC infections is hindered by the lack of knowledge about (i) the diversity, structure and identity of cell surface polymers expressed on Enterococcus spp. and ExPEC, (ii) how these polymers determine the biological niche a strain inhibits or the type of infection it causes, and (iii) what polymers to target to distinguish between beneficial and harmful strains. In BESPOKE we will explore and exploit bacterial cell surface polymers of Enterococcus spp. and ExPEC in an unprecedented manner. Using a bottom-up approach - from genome, to enzyme, to polymer – we aim to synthesize and structurally characterize the cell surface polymers in a pathogen-free way to elucidate the structural diversity that is presented to the human immune system during various types of infection. In addition, we will explore and biochemically investigate the as yet poorly understood cell wall polymer biosynthesis machineries on genome and enzyme level to make them available as marker for the surveillance of local epidemiology and as synthesis tools for biotechnological exploitation. Finally, we aim to build a highly versatile mix-and-match platform for the synthesis of glycoconjugate vaccines against bacterial infections that will help fight AMR and allow to respond quickly to local changes in epidemiology.