The emergence of extensively drug-resistant tuberculosis (XDR-TB) demands the need to identify new anti-tuberculosis drug targets as well as to better understand essential biosynthetic pathways. a-Glucan biosynthesis in Mycobacterium tuberculosis (Mtb) utilizes the maltosyltransferase GlgE which has been found to be essential and is also responsible for a portion of  a-glucan synthesis. The enzyme exhibits an a-retaining catalytic mechanism and usies maltose-1-phosphate (M1P) as a glycosyl donor substrate. Deletion of GlgE in Mtb results in the accumulation of M1P within cellsleading to a rapid death of the organism. To inhibit GlgE a non-covalent inhibitor maltose-C-phosphonate (MCP) was designed to act as an isosteric non-hydrolysable mimic of M1P.  MCP, the only known inhibitor of Mtb GlgE, was successfully synthesized using a Wittig olefination as a key step starting from maltose. MCP inhibited Mtb GlgE with an IC50 = 230 � 24 �M determined using a free phosphate assay. Development of the assay also resulted in a novel synthetic route to M1P from an intermediate used in MCP synthesis. In conclusion, we designed a substrate analogue of M1P which inhibited Mtb GlgE for the first time.

Synthesis of a C-phosphonate mimic of maltose-1-phosphate and inhibition studies on <i>Mycobacterium tuberculosis</i> GlgE

247th National Meeting (2014)

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Synthesis of a C-phosphonate mimic of maltose-1-phosphate and inhibition studies on Mycobacterium tuberculosis GlgE