Open AccessTargeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors
Author(s) -
Matthew R. Bockman,
Alvin S. Kalinda,
Riccardo Petrelli,
T. De la Mora-Rey,
Divya Tiwari,
Feng Liu,
Surrendra Dawadi,
Madhumitha Nandakumar,
Kyu Y. Rhee,
Dirk Schnappinger,
B.C. Finzel,
Courtney C. Aldrich
Publication year - 2015
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.5b00719
Subject(s) - chemistry , biotin , biotinylation , mycobacterium tuberculosis , dna ligase , biochemistry , nucleoside , enzyme , isothermal titration calorimetry , adenylylation , nucleoside triphosphate , nucleotide , tuberculosis , biosynthesis , medicine , pathology , gene
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 K(D)s ≤ 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.