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A new synthetic approach toward the bacterial transglycosylase substrates, Lipid II (1) and Lipid IV (2), is described. The key disaccharide was synthesized using the concept of relative reactivity value (RRV) and elaborated to Lipid II and Lipid IV by conjugation with the appropriate oligopeptides and pyrophosphate lipids. Interestingly, the results from our HPLC-based functional TGase assay suggested Lipid IV has a higher affinity for the enzyme than Lipid II.

The development of iminocyclitol-based small molecule libraries against a bacterial TGase is described. An iminocyclitol was conjugated with a pyrophosphate mimic using either a 1,3-dipolar cycloaddition or reductive amination reaction, which was then condensed with a variety of lipophilic carboxylic acids in an amide bond coupling to generate a desired molecular library. With assistance of microtiter plate-based combinatorial chemistry and in situ screening, a potential inhibitor, the first potent iminocyclitol-based inhibitor against bacterial TGases was efficiently developed.