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Tuberculosis (TB) remains a leading cause of mortality worldwide. With the emergence of multidrug resistant TB, extensively drug resistant TB and HIV-associated TB it is imperative that new drug targets be identified. The potential of  Mycobacterium tuberculosis  inosine monophosphate dehydrogenase (IMPDH) as a novel drug target was explored in the present study. IMPDH exclusively catalyzes the conversion of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) in the presence of the cofactor nicotinamide adenine dinucleotide (NAD + ). Although the enzyme is a dehydrogenase, the enzyme does not catalyze the reverse reaction i.e. the conversion of XMP to IMP. Unlike other bacteria,  M. tuberculosis  harbors three IMPDH-like genes, designated as Mt- guaB1 , Mt- guaB2  and Mt- guaB3  respectively. Of the three putative IMPDH's, we previously confirmed that Mt-GuaB2 was the only functional ortholog by characterizing the enzyme kinetically. Using an  in silico  approach based on designed scaffolds, a series of novel classes of inhibitors was identified. The inhibitors possess good activity against  M. tuberculosis  with MIC values in the range of 0.4 to 11.4 µg mL −1 . Among the identified ligands, two inhibitors have nanomolar  K i  s against the Mt-GuaB2 enzyme.

Identification of Novel Mt-Guab2 Inhibitor Series Active against M. tuberculosis