Inhibitors of Transketolase from Mycobacterium tuberculosis Targeted towards both the Diphosphate Binding Site and an Adjacent Hydrophobic Subsite

Transketolase from Mycobacterium tuberculosis (mbTK) is involved in the pentose phosphate pathway essential for bacterial survival and thus constitutes an attractive target for the antituberculosis therapy. We found a new class of active site-targeted furan sulfonate inhibitors of mbTK that are capable of binding to both the thiamine diphosphate cofactor subsite and adjacent hydrophobic subsite Ile211-Leu402-Phe464, thereby suppressing enzyme activity. The most potent compound identified by computer screening, STK106769, was found to inhibit mbTK with IC₅₀ of 7 µM and suppress the growth of M. tuberculosis H37Rv strain. The hydrophobic subsite Ile211-Leu402-Phe464 of mbTK is substituted by significantly more polar residues in homologous human TK, which is an important factor determining the selectivity of binding of TK inhibitors.