Maloy K. Parai

Low Frequency of Resistance, No Cross-Resistance, and Combination Potential of TAM16 Low Frequency of Resistance, No Cross-Resistance, and Combination Potential of TAM16 The TE domain construct corresponding to the predicted TE domain in Mtb pks13 gene (Rv3800c) was made by PCR from the Mtb H37Rv genomic DNA as the template (forward primer: 5? – TAC TTC CAA TCC AAT GCC CAG ATC GAT GGG TTC GTC CGC AC – 3?, reverse primer: 5? – TTA TCC ACT TCC AAT GTT ATC ACT GCT TGC CTA CCT CAC TTG TTC G – 3?).

Fragment screening and high throughput screening are complementary approaches that combine with structural biology to explore the binding capabilities of an active site. We have used a fragment-based approach on malate synthase (GlcB) from Mycobacterium tuberculosis and discovered several novel binding chemotypes. In addition, the crystal structures of GlcB in complex with these fragments indicated conformational changes in the active site that represent the enzyme conformations during catalysis.

Author contributions: IVK and JCS conceived the idea of the project; HLH conducted the fragment screening and obtained crystal structures of complexes with fragments and an inhibitor; IVK obtained the structures of complexes with inhibitors as well as GlcB complexed with products and apo structures; enzyme purification and activity assays were done by HLH and IVK; indole compounds were synthesized by VBJ and MKP; the manuscript was prepared by HLH, IVK and JCS.