Mycobacterium tuberculosis (Mtb) is responsible for both latent and symptomatic tuberculosis (TB). TB remains the second leading cause of mortality among infectious diseases worldwide, primarily due to the emergence of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains. To combat this pathogen, the development of new antitubercular agents is essential. Mycobacterial biotin protein ligase (MtBPL) regulates lipid metabolism in Mtb through the post-translational biotinylation of acyl coenzyme A carboxylases that catalyze the initial step in fatty acid biosynthesis. Additionally, MtBPL biotinylates pyruvate coenzyme A carboxylase, a gluconeogenic enzyme integral for lipid catabolism. We will present the synthesis as well as biochemical and structural characterization of a systematic series of bisubstrate biotin-nucleoside inhibitors with modifications to the ribofuranosyl ring. Several of these inhibitors including ribofuranosyl, 3′-deoxy, acyclo and morpholino analogs display sub-nanomolar inhibition of MtBPL as determined by isothermal titration calorimetry (ITC) and potent whole-cell activity against Mtb. While many analogs exhibit less than five-fold decrease in potency or are equipotent to the parent inhibitor containing a ribofuranose ring, certain modifications including the 2′-β-fluoro, 2′-β-azido, 2′-bβ-methyl and carbocycle completely abolish activity in whole-cell assays. The lack of correlation between biochemical and whole-cell activity suggests certain modifications severely impede intracellular accumulation.

Targeting Mycobacterium tuberculosis biotin protein ligase (MtBPL): Synthesis and evaluation of nucleoside-based bisubstrate adenylation inhibitors

249th National Meeting (2015)

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