Researchers using the GM/CA-XSD 23-ID-B beamline at the APS are targeting Mycobacterium tuberculosis (Mtb) by focusing on Mycobacterial Biotin Protein Ligase (MtBPL), an essential enzyme in Mtb that regulates lipid metabolism. The findings have been published in The Journal of Medicinal Chemistry.
Tuberculosis (TB) is a leading cause of bacterial infectious disease mortality and morbidity. The bacillus Mycobacterium tuberculosis (Mtb) is responsible for both latent and symptomatic TB and belongs to the greater Mycobacterium tuberculosis complex. Researchers seek to develop new classes of anti-tubercular agents for this worldwide clinical need that are effective against drug-resistant TB and ideally possess a novel mode of action.
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 KD’s below 2 nM. Additionally, we obtained high-resolution co-crystal 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 in Mtb showed a nearly 10-fold enhanced accumulation of a C-2′-α analog over the corresponding C-2′-β analog, consistent with their differential whole-cell activity.
Matthew R. Bockman, Alvin S. Kalinda, Riccardo Petrelli, Teresa De la Mora-Rey, Divya Tiwari, Feng Liu, Surendra Dawadi, Madhumitha Nandakumar, Kyu Y. Rhee, Dirk Schnappinger, Barry C. Finzel and Courtney C. Aldrich, “Targeting Mycobacterium tuberculosis Biotin Protein Ligase with Nucleoside-Based Bisubstrate Adenylation Inhibitors,” The Journal of Medicinal Chemistry, Article. Just Accepted Manuscript. DOI: 10.1021/acs.jmedchem.5b00719. Published Online August 24, 2015.