Tuberculosis (TB), which is caused by the bacterium Mycobacterium tuberculosis (Mtb), is a major health issue in many parts of the world. Mtb’s complex cell wall contributes to its pathogenesis and resistance to antibiotics so it represents an important target for TB drug and diagnostic development. Trehalose is a non-mammalian disaccharide that is required for the construction of various cell wall components in Mtb. A trehalose-recycling transporter, SugABC-LpqY, was recently discovered in Mtb and shown to be essential for virulence. Here, we report the development of chemical methods to investigate the substrate specificity of SugABC-LpqY. Trehalose analogues with structural modifications at various positions on the disaccharide were synthesized using a chemoenzymatic method and several were tested for uptake by SugABC-LpqY. We also synthesized a 13C-labeled version of trehalose to enable quantitative comparisons of uptake between trehalose analogues and the natural substrate trehalose. Based on the results obtained so far, it appears that SugABC-LpqY exhibits good substrate tolerance for small structural modifications (e.g., fluoro-, azido-, and deoxy- modifications). These results should facilitate the exploitation of SugABC-LpqY for the delivery of trehalose-based probes or inhibitors specifically to Mtb during infection.

Investigating the substrate specificity of the trehalose-recycling transporter SugABC-LpqY

251st National Meeting (2016)

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