Bisubstrate inhibitors of biotin protein ligase in mycobacterium tuberculosis resistant to cyclonucleoside formation

Ce Shi, Divya Tiwari, Daniel J. Wilson, Christopher L. Seiler, Dirk Schnappinger, Courtney C. Aldrich

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, is the leading cause of bacterial infectious disease mortality. Biotin protein ligase (BirA) globally regulates lipid metabolism in Mtb through the posttranslational biotinylation of acyl coenzyme A carboxylases (ACCs) involved in lipid biosynthesis and is essential for Mtb survival. 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 resistant Mtb strains. 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 a bulky group on the nucleobase to prevent the required syn-conformation necessary for proper alignment of N-3 with C-5′.

Original languageEnglish (US)
Pages (from-to)1213-1217
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume4
Issue number12
DOIs
StatePublished - Dec 12 2013

Keywords

  • Adenylate-forming
  • adenylation
  • antibiotic
  • biotin protein ligase
  • isothermal titration calorimetry
  • tuberculosis

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