Synthesis of activated 6-deoxy-6-fluorosugars: biomimetic feedstocks for combinatorial biosynthesis

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In Nature, valuable classes of antibiotic molecules are biosynthesised from an aglycone component (usually a large complex cyclic molecule) which is glycosylated with one or more modified sugar molecules. This glycosylation event is essential for activity, and is also a potential source of the novel antibiotics which could show improved properties, most importantly for the treatment of multidrug-resistant bacterial strains which are becoming increasingly problematic.Because of their complexity, chemical synthesis of these potential new agents is very challenging; however, if the machinery of nature can be used to add unnatural sugars to aglycones, we could discover novel agents considerably more easily. This activity requires the synthesis of the unnatural sugars, their activation to NDP sugars suitable for processing by a glycosyl transferase (GT) enzyme and their transfer to the aglycone. Our proposed programme combines all these elements. Chemical synthesis is used to prepare the unnatural sugars, while chemoenzymatic and enzymatic methods will be used to activate them. We will then explore the use of a range of commercial, proprietary and research GTs to transfer unnatural sugars to aglycones. Fluorosugars are used because they are unknown in nature and are expected to confer useful properties on the glycosylatedmolecules.