title: Bisubstrate Inhibitors of Biotin Protein Ligase inMycobacterium tuberculosisResistant to Cyclonucleoside Formation.
abstract: Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, is the leading cause bacterial infectious diseases mortality. Biotin protein ligase (BirA) globally regulates lipid metabolism inMtbthrough the posttranslational biotinylation of acyl coenzyme A carboxylases (ACCs) involved in lipid biosynthesis and is essential forMtbsurvival. We previously developed a rationally designed bisubstrate inhibitor of BirA that displays potent enzyme inhibition and whole-cell activity against multidrug resistant and extensively drug resistantMtbstrains. Here we present the design, synthesis and evaluation of a focused series of inhibitors, which are resistant to cyclonucleoside formation, a key decomposition pathway of our initial analogue. Improved chemical stability is realized through replacement of the adenosyl N-3 nitrogen and C-5' oxygen atom with carbon as well as incorporation of bulky group on the nucleobase to prevent the requiredsyn-conformation necessary for proper alignment of N-3 with C-5'.
authors.affiliation: Center for Drug Design, University of Minnesota, Minneapolis, MN, 55455, USA ; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, 55455, USA.
authors.forename: Ce
authors.initials: C
authors.lastname: Shi
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, 10065, USA.
authors.forename: Divya
authors.initials: D
authors.lastname: Tiwari
authors.affiliation: Center for Drug Design, University of Minnesota, Minneapolis, MN, 55455, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wilson
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, 55455, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Seiler
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, 10065, USA.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schnappinger
authors.affiliation: Center for Drug Design, University of Minnesota, Minneapolis, MN, 55455, USA ; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, 55455, USA.
authors.forename: Courtney C
authors.initials: CC
authors.lastname: Aldrich
keywords: adenylate-forming; adenylation; antibiotic; biotin protein ligase; isothermal titration calorimetry; tuberculosis