glycogen and Tuberculosis

Tuberculosis continues to be a deadly infectious disease, mainly due to the existence of persistent bacterial populations that survive drug treatment and obstruct complete eradication of infection. The enzymes GlgE and GlgB, which are involved in the glycan pathway, have recently been identified as promising drug targets for combating persistent bacillus strains. In the glycan pathway, enzymes GlgE, GlgA, and Tre-xyz produce linear α-glucans, which are then converted to essential branched α-glucan by GlgB. This α-glucan is a vital cell-wall and storage polysaccharide, critical for Mtb virulence and persistence. We highlight recent insights into the significance of both GlgE and GlgB in the glycan pathway and also discuss drug strategies for tuberculosis such as polypharmcological targeting of GlgB and GlgE. Small molecule-based modulation of GlgB and GlgE to boost the design and development of novel and improved drugs for more selective and efficient targeting of tuberculosis are also discussed.

Topics: 1,4-alpha-Glucan Branching Enzyme; Antitubercular Agents; Bacterial Proteins; Binding Sites; Glycogen; Humans; Molecular Dynamics Simulation; Mycobacterium tuberculosis; Protein Structure, Tertiary; Tuberculosis

Topics: Alkaline Phosphatase; Animals; Brain Edema; Cerebrovascular Disorders; Epilepsy; Glycogen; Guinea Pigs; Hematologic Diseases; Humans; Leukocytes; Neoplasms; Rabbits; Tuberculosis; Wounds and Injuries

Mycobacterium tuberculosis and other pathogenic mycobacterial species produce large amounts of a glycogen-like alpha-glucan that represents the major polysaccharide of their outermost capsular layer. To determine the role of the surface-exposed glucan in the physiology and virulence of these bacteria, orthologues of the glg genes involved in the biosynthesis of glycogen in Escherichia coli were identified in M. tuberculosis H37Rv and inactivated by allelic replacement. Biochemical analyses of the mutants and complemented strains indicated that the synthesis of glucan and glycogen involves the alpha-1,4-glucosyltransferases Rv3032 and GlgA (Rv1212c), the ADP-glucose pyrophosphorylase GlgC (Rv1213) and the branching enzyme GlgB (Rv1326c). Disruption of glgC reduced by half the glucan and glycogen contents of M. tuberculosis, whereas the inactivation of glgA and Rv3032 affected the production of capsular glucan and glycogen, respectively. Attempts to disrupt Rv3032 in the glgA mutant were unsuccessful, suggesting that a functional copy of at least one of the two alpha-1,4-glucosyltransferases is required for growth. Importantly, the glgA mutant was impaired in its ability to persist in mice, suggesting a role for the capsular glucan in the persistence phase of infection. Unexpectedly, GlgB was found to be an essential enzyme.

Topics: 1,4-alpha-Glucan Branching Enzyme; Animals; Bacterial Proteins; Cells, Cultured; DNA, Bacterial; Female; Gene Knockout Techniques; Genes, Bacterial; Genetic Complementation Test; Glucans; Glucose-1-Phosphate Adenylyltransferase; Glycogen; Macrophages; Mice; Mice, Inbred BALB C; Mutation; Mycobacterium tuberculosis; Tuberculosis

Topics: Alkaline Phosphatase; Animals; Chymotrypsin; DNA; Glycogen; Guinea Pigs; Kidney; Liver; Lung; Mycobacterium bovis; Myocardium; RNA; Spleen; Streptomycin; Sulfhydryl Compounds; Tuberculosis

Topics: Animals; BCG Vaccine; Glycogen; Guinea Pigs; Neutrophils; Tuberculin; Tuberculosis

Topics: Alkaline Phosphatase; Animals; DNA; Glycogen; Glycosaminoglycans; Guinea Pigs; Histocytochemistry; Kidney; Liver; Spleen; Sulfhydryl Compounds; Tuberculosis

Topics: Alkaline Phosphatase; Animals; Glycogen; Guinea Pigs; Leukocytes; Peroxidases; Phagocytosis; Tuberculosis

Topics: Animals; Biological Assay; Exudates and Transudates; Genetics; Glycogen; Leukocytes; Macrophages; Mineral Oil; Muramidase; Rabbits; Research; Sarcina; Toxicology; Tuberculosis

Topics: Glycogen; Glycosaminoglycans; Histocytochemistry; Humans; Tuberculosis; Tuberculosis, Pulmonary

Topics: Glucosyltransferases; Glycogen; Guinea Pigs; Liver; Liver Glycogen; Phosphoglucomutase; Phosphoric Monoester Hydrolases; Phosphotransferases; Tuberculosis

Topics: Animals; Carbohydrate Metabolism; Exudates and Transudates; Glycogen; Glycogenolysis; Guinea Pigs; Hexosephosphates; Peritoneal Cavity; Phosphorus Isotopes; Radioisotopes; Research; Tuberculin; Tuberculosis

Topics: Cholesterol; Glycogen; Glycogenolysis; Humans; Hypersensitivity; Tuberculosis

Topics: Blood Glucose; Exudates and Transudates; Glycogen; Hematologic Tests; Humans; Leukocytes; Tuberculosis; Tuberculosis, Pulmonary

Topics: Animals; Bacillus; Glycogen; Guinea Pigs; Hot Temperature; Immunization; Tuberculosis

Topics: Animals; Bacillus; Glycogen; Hot Temperature; Immunization; Mice; Rabbits; Tuberculosis