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Bisubstrate adenylation inhibitors of biotin protein ligase from Mycobacterium tuberculosis.

TitleBisubstrate adenylation inhibitors of biotin protein ligase from Mycobacterium tuberculosis.
Publication TypeJournal Article
Year of Publication2011
AuthorsDuckworth BP, Geders TW, Tiwari D, Boshoff HI, Sibbald PA, Barry CE, Schnappinger D, Finzel BC, Aldrich CC
JournalChem Biol
Volume18
Issue11
Pagination1432-41
Date Published2011 Nov 23
ISSN1879-1301
KeywordsAntitubercular Agents, Bacterial Proteins, Binding Sites, Carbon-Nitrogen Ligases, Crystallography, X-Ray, Drug Design, Drug Resistance, Bacterial, Enzyme Activation, Enzyme Inhibitors, Kinetics, Microbial Sensitivity Tests, Mycobacterium tuberculosis, Protein Structure, Tertiary, Structure-Activity Relationship, Substrate Specificity, Thermodynamics
Abstract

The mycobacterial biotin protein ligase (MtBPL) globally regulates lipid metabolism in Mtb through the posttranslational biotinylation of acyl coenzyme A carboxylases involved in lipid biosynthesis that catalyze the first step in fatty acid biosynthesis and pyruvate coenzyme A carboxylase, a gluconeogenic enzyme vital for lipid catabolism. Here we describe the design, development, and evaluation of a rationally designed bisubstrate inhibitor of MtBPL. This inhibitor displays potent subnanomolar enzyme inhibition and antitubercular activity against multidrug resistant and extensively drug resistant Mtb strains. We show that the inhibitor decreases in vivo protein biotinylation of key enzymes involved in fatty acid biosynthesis and that the antibacterial activity is MtBPL dependent. Additionally, the gene encoding BPL was found to be essential in M. smegmatis. Finally, the X-ray cocrystal structure of inhibitor bound MtBPL was solved providing detailed insight for further structure-activity analysis. Collectively, these data suggest that MtBPL is a promising target for further antitubercular therapeutic development.

DOI10.1016/j.chembiol.2011.08.013
Alternate JournalChem Biol
PubMed ID22118677
PubMed Central IDPMC3225891
Grant ListR01 AI091790 / AI / NIAID NIH HHS / United States
R01 AI091790-01 / AI / NIAID NIH HHS / United States
AI-091790 / AI / NIAID NIH HHS / United States
/ / Wellcome Trust / United Kingdom

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