Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors

Mycobacterium tuberculosis (Mtb), responsible for both latent and symptomatic
tuberculosis
(TB), remains the second leading cause of mortality among infectious
diseases worldwide. Mycobacterial biotin protein ligase (MtBPL) is an essential enzyme in Mtb and regulates
lipid metabolism through the post-translational biotinylation of acyl
coenzyme A carboxylases. We report the synthesis and evaluation of
a systematic series of potent nucleoside-based inhibitors of MtBPL that contain modifications to the ribofuranosyl ring
of the nucleoside. All compounds were characterized by isothermal
titration calorimetry (ITC) and shown to bind potently with KDs ≤ 2 nM. Additionally, we obtained
high-resolution cocrystal structures for a majority of the compounds.
Despite fairly uniform biochemical potency, the whole-cell Mtb activity varied greatly with minimum inhibitory concentrations
(MIC) ranging from 0.78 to >100 μM. Cellular accumulation
studies
showed a nearly 10-fold enhancement in accumulation of a C-2′-α
analogue over the corresponding C-2′-β analogue, consistent
with their differential whole-cell activity.