title: Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors.
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.
authors: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
authors: Matthew R
authors: MR
authors: Bockman
authors: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.|Center for Drug Design, Academic Health Center, University of Minnesota, MN 55455 USA.
authors: Alvin S
authors: AS
authors: Kalinda
authors: Center for Drug Design, Academic Health Center, University of Minnesota, MN 55455 USA.
authors: Riccardo
authors: R
authors: Petrelli
authors: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
authors: Teresa
authors: T
authors: De la Mora-Rey
authors: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10021, USA.
authors: Divya
authors: D
authors: Tiwari
authors: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
authors: Feng
authors: F
authors: Liu
authors: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
authors: Surrendra
authors: S
authors: Dawadi
authors: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10021, USA.
authors: Madhumitha
authors: M
authors: Nandakumar
authors: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10021, USA.
authors: Kyu Y
authors: KY
authors: Rhee
authors: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10021, USA.
authors: Dirk
authors: D
authors: Schnappinger
authors: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
authors: Barry C
authors: BC
authors: Finzel
authors: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.|Center for Drug Design, Academic Health Center, University of Minnesota, MN 55455 USA.
authors: Courtney C
authors: CC
authors: Aldrich
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019921:Biotinylation; D019731:Carbon-Nitrogen Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D009705:Nucleosides; D019731:Carbon-Nitrogen Ligases