Open AccessBisubstrate Inhibitors of Biotin Protein Ligase in Mycobacterium tuberculosis Resistant to Cyclonucleoside Formation
Author(s) -
Ce Shi,
Divya Tiwari,
Daniel J. Wilson,
Charles E. Seiler,
Dirk Schnappinger,
Courtney C. Aldrich
Publication year - 2013
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml400328a
Subject(s) - dna ligase , biotin , biotinylation , biochemistry , mycobacterium tuberculosis , enzyme , cofactor , coenzyme a , chemistry , ubiquitin ligase , mycobacterium , biosynthesis , biology , tuberculosis , bacteria , ubiquitin , medicine , gene , genetics , pathology , reductase
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'.