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

TitleTargeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors.
Publication TypeJournal Article
Year of Publication2015
AuthorsBockman MR, Kalinda AS, Petrelli R, De la Mora-Rey T, Tiwari D, Liu F, Dawadi S, Nandakumar M, Rhee KY, Schnappinger D, Finzel BC, Aldrich CC
JournalJ Med Chem
Volume58
Issue18
Pagination7349-7369
Date Published2015 Sep 24
ISSN1520-4804
KeywordsAntitubercular Agents, Bacterial Proteins, Biotinylation, Carbon-Nitrogen Ligases, Crystallography, X-Ray, Microbial Sensitivity Tests, Models, Molecular, Mycobacterium tuberculosis, Nucleosides, Protein Conformation, Stereoisomerism, Structure-Activity Relationship, Thermodynamics
Abstract

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.

DOI10.1021/acs.jmedchem.5b00719
Alternate JournalJ Med Chem
PubMed ID26299766
PubMed Central IDPMC4667793
Grant ListCA-77598 / CA / NCI NIH HHS / United States
P30 CA077598 / CA / NCI NIH HHS / United States
AI091790 / AI / NIAID NIH HHS / United States
S10 OD017982 / OD / NIH HHS / United States
R01 AI091790 / AI / NIAID NIH HHS / United States
S10-OD017982 / OD / NIH HHS / United States

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