The glycocalyx is a complex layer of glycoconjugates that covers the surface of our cells. Sialic acid containing glycans (e.g. NeuAc2-3Gal, sialyl lactose, sLex), due to their terminal locality play a role in important cell-cell interactions, but also interactions with many pathogens. Lectins that recognise carbohydrates often bind oligosaccharides in a single conformation. Glycomimetics preorganised into the preferred binding orientation by constraining the glycosidic linkage may reduce the entropic penalty, resulting in stronger interactions with the lectin. Sia2-3Gal oligosaccharides have two low energy conformers and it would be desirable to constrain Sia2-3Gal into the conformer recognised by proteins (Fig 1A). The evolutionary stress placed upon bacteria by conventional antibiotics has given rise to resistant strains that are becoming increasingly hard to treat, with MRSA a prime example. This has accelerated the search for alternative therapeutics and targets. Members of the Staph. aureus family produce a range of proteins which influences the onset of infection. One such protein, SSL11, binds the Sia2-3Gal oligosaccharides and has been shown to play a key role in pathogenesis including bacterial adhesion and hindering of the body’s natural immune system. Inhibiting this protein could have a profound impact in combatting bacterial infection. This work involves the synthesis of novel compounds mimicking Sia2-3Gal, (the minimum binding epitope for SSL11) constrained into a single conformation, as confirmed by molecular dynamics simulations. The protein of interest, SSL11, was recombinantly expressed and isolated to a high degree of purity and was then crystallised in the presence of the glycomimetic and the crystal structure revealed interactions of the complex. Further synthesis involving the rational based drug design stemming from the data obtained from this crystal structure will also be presented. Finally, the biophysical evaluation using isothermal titration calorimetry of natural oligosaccharides as well as glycomimetics against SSL11, a technique which has not yet been used to study interactions of glycans with this protein.

Synthesis and evaluation of glycomimetics as inhibitors of Staphylococcus aureus

ACS Fall 2021

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