Bisubstrate Adenylation Inhibitors of Biotin Protein Ligase from Mycobacterium tuberculosis

SummaryThe 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.

Graphical AbstractFigure optionsDownload high-quality image (137 K)Download as PowerPoint slideHighlights
► Redesigned bisubstrate inhibitor displays pM binding affinity for Mtb Biotin Protein Ligase (BPL)
► Inhibitor shows selective whole-cell antitubercular activity
► Gene encoding BPL shown to be essential in M. smegmatis
► Cocrystal structure of inhibitor bound to BPL solved