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Bisubstrate Inhibitors of Biotin Protein Ligase in Mycobacterium tuberculosis Resistant to Cyclonucleoside Formation.

TitleBisubstrate Inhibitors of Biotin Protein Ligase in Mycobacterium tuberculosis Resistant to Cyclonucleoside Formation.
Publication TypeJournal Article
Year of Publication2013
AuthorsShi C, Tiwari D, Wilson DJ, Seiler CL, Schnappinger D, Aldrich CC
JournalACS Med Chem Lett
Volume4
Issue12
Date Published2013 Dec 12
ISSN1948-5875
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 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 bulky group on the nucleobase to prevent the required syn-conformation necessary for proper alignment of N-3 with C-5'.

DOI10.1021/ml400328a
Alternate JournalACS Med Chem Lett
PubMed ID24363833
PubMed Central IDPMC3867986
Grant ListR01 AI091790 / AI / NIAID NIH HHS / United States

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