The long-term objective of this project is to study the roles of sulfated and sulfur-containing metabolites in the life cycle and pathogenesis of Mycobacterium tuberculosis (M. tb). Mycobacterial pathogens have been declared a global emergency by the World Health Organization, particularly in regard to the deadly synergy of M. tb and M. avium with AIDS. The emergence of multidrug resistant strains of both M. tb and M. avium has further escalated the need for new therapeutic avenues. M. tb infection is a complex process that involves residence within lung macrophages, stimulation of an immune response and the formation of granulomas, entry into a latent phase and, ultimately, emergence from latency to produce active tuberculosis. Complex interactions between the pathogen and its host are required to sustain the various stages of the life cycle. This project was initiated by our discovery of putative sulfotransferases and sulfatases in mycobacterial genomes. A handful of sulfated metabolites had been identified in mycobacteria, including the abundant cell wall glycolipid sulfolipid-1 (SL-1), but their functions were unknown. In eukaryotes, sulfated metabolites are known to play roles in cell-cell communication. We therefore speculated that the sulfated metabolites in mycobacteria may be involved in host-pathogen interactions. The last granting period focused on three Specific Aims: 1) define the functions of mycobacterial sulfotransferases; 2) investigate the functions of mycobacterial sulfatases; and 3) define the sulfur assimilation pathway in Mycobacterium tuberculosis. In the next granting period we plan to continue our studies of the mycobacterial sulfate metabolic machinery. We will investigate the biological roles of sulfated metabolites and the associated biosynthetic enzymes in both M. tb and M.
avium (Aim 1). We will study M. tb sulfation mutants in cell-based assays and immune-compromised mice in order to assess interactions with adaptive and innate immune mechanisms (Aim 2). Small molecule inhibitors of APS reductase will be sought as tools for functional studies and leads for drug development (Aim 3). Finally, we will further characterize mycobacterial formylglycine generating enzymes and sulfatases (Aim 4). ? ? ?
| Rodriguez-Rivera, Frances P; Zhou, Xiaoxue; Theriot, Julie A et al. (2018) Acute Modulation of Mycobacterial Cell Envelope Biogenesis by Front-Line Tuberculosis Drugs. Angew Chem Int Ed Engl 57:5267-5272 |
| Kamariza, Mireille; Shieh, Peyton; Ealand, Christopher S et al. (2018) Rapid detection of Mycobacterium tuberculosis in sputum with a solvatochromic trehalose probe. Sci Transl Med 10: |
| Kamariza, Mireille; Shieh, Peyton; Bertozzi, Carolyn R (2018) Imaging Mycobacterial Trehalose Glycolipids. Methods Enzymol 598:355-369 |
| Schump, Michael D; Fox, Douglas M; Bertozzi, Carolyn R et al. (2017) Subcellular Partitioning and Intramacrophage Selectivity of Antimicrobial Compounds against Mycobacterium tuberculosis. Antimicrob Agents Chemother 61: |
| Rodriguez-Rivera, Frances P; Zhou, Xiaoxue; Theriot, Julie A et al. (2017) Visualization of mycobacterial membrane dynamics in live cells. J Am Chem Soc 139:3488-3495 |
| Ganesan, Lakshmi; Shieh, Peyton; Bertozzi, Carolyn R et al. (2017) Click-Chemistry Based High Throughput Screening Platform for Modulators of Ras Palmitoylation. Sci Rep 7:41147 |
| Sogi, Kimberly M; Holsclaw, Cynthia M; Fragiadakis, Gabriela K et al. (2016) Biosynthesis and Regulation of Sulfomenaquinone, a Metabolite Associated with Virulence in Mycobacterium tuberculosis. ACS Infect Dis 2:800-806 |
| Ngo, John T; Adams, Stephen R; Deerinck, Thomas J et al. (2016) Click-EM for imaging metabolically tagged nonprotein biomolecules. Nat Chem Biol 12:459-65 |
| Touchette, Megan H; Holsclaw, Cynthia M; Previti, Mary L et al. (2015) The rv1184c locus encodes Chp2, an acyltransferase in Mycobacterium tuberculosis polyacyltrehalose lipid biosynthesis. J Bacteriol 197:201-10 |
| Siegrist, M Sloan; Swarts, Benjamin M; Fox, Douglas M et al. (2015) Illumination of growth, division and secretion by metabolic labeling of the bacterial cell surface. FEMS Microbiol Rev 39:184-202 |
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