Inhibition of Cytokine Release by Mycobacterium tuberculosis Phenolic Glycolipid Analogues

Infection by Mycobacterium tuberculosis causes tuberculosis, a disease characterized by alteration of host innate and adaptive immunity. These processes are mediated by a series of bacterial biomolecules, among which phenolic glycolipids (PGLs) and the related p‐hydroxybenzoic acid derivatives have been suggested to play important roles. To probe the importance of structural features of these glycans on cytokine modulation, we synthesized three M. tuberculosis PGL analogues ( 1 – 3 ), which differ from the native glycoconjugates by possessing a simplified lipid algycone. The ability of 1 – 3 to modulate the release of proinflammatory cytokines (TNF‐α, IL‐1β, IL‐6, MCP‐1) and nitric oxide (NO) was evaluated. None of the compounds stimulated the secretion of these signalling molecules. However, all showed a Toll‐like Receptor 2‐mediated, concentration‐dependent inhibition profile that was related to the methylation pattern on the glycan.     

Chemoenzymatic Synthesis of Trehalose Analogues: Rapid Access to Chemical Probes for Investigating Mycobacteria

Trehalose analogues are emerging as valuable tools for investigating Mycobacterium tuberculosis, but progress in this area is slow due to the difficulty in synthesizing these compounds. Here, we report a chemoenzymatic synthesis of trehalose analogues that employs the heat‐stable enzyme trehalose synthase (TreT) from the hyperthermophile Thermoproteus tenax. By using TreT, various trehalose analogues were prepared quickly (1 h) in high yield (up to >99 % by HPLC) in a single step from readily available glucose analogues. To demonstrate the utility of this method in mycobacteria research, we performed a simple “one‐pot metabolic labeling” experiment that accomplished probe synthesis, metabolic labeling, and imaging of M. smegmatis in a single day with only TreT and commercially available materials.     

Immunometabolism of Myeloid-Derived Suppressor Cells: Implications for Mycobacterium tuberculosis Infection and Insights from Tumor Biology

The field of immunometabolism seeks to decipher the complex interplay between the immune system and the associated metabolic pathways. The role of small molecules that can target specific metabolic pathways and subsequently alter the immune landscape provides a desirable platform for new therapeutic interventions. Immunotherapeutic targeting of suppressive cell populations, such as myeloid-derived suppressor cells (MDSC), by small molecules has shown promise in pathologies such as cancer and support testing of similar host-directed therapeutic approaches in MDSC-inducing conditions such as tuberculosis (TB). MDSC exhibit a remarkable ability to suppress T-cell responses in those with TB disease. In tumors, MDSC exhibit considerable plasticity and can undergo metabolic reprogramming from glycolysis to fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) to facilitate their immunosuppressive functions. In this review we look at the role of MDSC during M. tb infection and how their metabolic reprogramming aids in the exacerbation of active disease and highlight the possible MDSC-targeted metabolic pathways utilized during M. tb infection, suggesting ways to manipulate these cells in search of novel insights for anti-TB therapies.     

Activity of Riminophenazines against Mycobacterium tuberculosis: A Review of Studies that Might be Contenders for Use as Antituberculosis Agents

Tuberculosis is one of the leading cause of death in the world, mainly due to the increasing number of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains. Factors such as the HIV pandemic contribute further. Also, the ineffectiveness of the chemotherapy in current use increases the mortality rate. Therefore, new and repurposed antituberculosis drugs are urgently needed for the treatment of MDR-TB, and riminophenazines are among those drugs that are being reinvestigated for their potential in the treatment of TB. This review delivers a brief historical account of riminophenazines, their general synthesis, mechanisms of action, and their physicochemical properties. The discussion is limited to those studies that investigated the activity of these compounds as antituberculosis agents. Given their unique properties, this review will be of great significance in giving direction towards the design and development of new riminophenazine analogues.