Goal: The overarching goal of this proposal is to better understand key steps in the utilization and recycling of trehalose in mycobacteria. The disaccharide trehalose is important for multiple aspects of mycobacterial physiology and has been shown to be essential for viability as is the downstream utilization pathway that leads to trehalose monomycolate production and export. Recycling of the trehalose used to build the outer membrane is important for M. tuberculosis virulence and is used to extend a-glucans that have various roles in the bacterium. This research project possesses 2 separate portions related to trehalose metabolism. The first portion of this study aims to develop novel classes of compounds that inhibit the three enzymes of the Antigen 85 Complex. Second, we will use our current knowledge of GlgE protein structure to develop second-generation inhibitors and improved tools for assessing the inhibitor activity of these inhibitors. Since inhibition of GlgE promotes rapid killing of M. tuberculosis, improving upon the current inhibitors will significantly advance our ability to treat TB. It is expected that results obtained from this study will extend the available M. tuberculosis drugs to include compounds that target trehalose biosynthesis and utilization.
The World Health Organization estimates that 1.4 million people each year die from Tuberculosis. The first-line drugs used to treat tuberculosis have been used for 50 years and strains resistant to these drugs are becoming much more common. This research aims to better characterize the bacterial enzymes necessary for sugar biosynthesis and to target these enzymes with new drugs to treat Tuberculosis.
|Goins, Christopher M; Dajnowicz, Steven; Smith, Micholas D et al. (2018) Mycolyltransferase from Mycobacterium tuberculosis in covalent complex with tetrahydrolipstatin provides insights into antigen 85 catalysis. J Biol Chem 293:3651-3662|
|Banco, Michael T; Mishra, Vidhi; Greeley, Samantha C et al. (2018) Direct Detection of Products from S-Adenosylmethionine-Dependent Enzymes Using a Competitive Fluorescence Polarization Assay. Anal Chem 90:1740-1747|
|Goins, Christopher M; Schreidah, Celine M; Dajnowicz, Steven et al. (2018) Structural basis for lipid binding and mechanism of the Mycobacterium tuberculosis Rv3802 phospholipase. J Biol Chem 293:1363-1372|
|Petit, Cecile; Kim, Younghwa; Lee, Sung-Kwon et al. (2018) Reduction of Feedback Inhibition in Homoserine Kinase (ThrB) of Corynebacterium glutamicum Enhances l-Threonine Biosynthesis. ACS Omega 3:1178-1186|
|Goins, Christopher M; Sudasinghe, Thanuja D; Liu, Xiaofan et al. (2018) Characterization of Tetrahydrolipstatin and Stereoderivatives on the Inhibition of Essential Mycobacterium tuberculosis Lipid Esterases. Biochemistry 57:2383-2393|
|Veleti, Sri Kumar; Petit, Cecile; Lindenberger, Jared J et al. (2017) Correction: Zwitterionic pyrrolidene-phosphonates: inhibitors of the glycoside hydrolase-like phosphorylase Streptomyces coelicolor GlgEI-V279S. Org Biomol Chem 15:6679|
|Veleti, Sri Kumar; Petit, Cecile; Ronning, Donald R et al. (2017) Zwitterionic pyrrolidene-phosphonates: inhibitors of the glycoside hydrolase-like phosphorylase Streptomyces coelicolor GlgEI-V279S. Org Biomol Chem 15:3884-3891|
|Goins, Christopher M; Dajnowicz, Steven; Thanna, Sandeep et al. (2017) Exploring Covalent Allosteric Inhibition of Antigen 85C from Mycobacterium tuberculosis by Ebselen Derivatives. ACS Infect Dis 3:378-387|
|Thanna, Sandeep; Goins, Christopher M; Knudson, Susan E et al. (2017) Thermal and Photoinduced Copper-Promoted C-Se Bond Formation: Synthesis of 2-Alkyl-1,2-benzisoselenazol-3(2H)-ones and Evaluation against Mycobacterium tuberculosis. J Org Chem 82:3844-3854|
|Thanna, Sandeep; Knudson, Susan E; Grzegorzewicz, Anna et al. (2016) Synthesis and evaluation of new 2-aminothiophenes against Mycobacterium tuberculosis. Org Biomol Chem 14:6119-6133|
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