Glucose phosphorylation is required for Mycobacterium tuberculosis persistence in mice

Area of Science:

• Microbiology
• Biochemistry
• Pathogenesis

Background:

• Mycobacterium tuberculosis (Mtb) primarily utilizes fatty acid metabolism for chronic infections.
• Mtb's metabolic flexibility allows co-catabolism of various carbon sources, including carbohydrates.
• The role of glucose metabolism in Mtb pathogenesis requires further investigation.

Purpose of the Study:

• To investigate the significance of glucose phosphorylation in Mtb's carbon metabolism and pathogenesis.
• To characterize the function of Mtb's two identified glucokinase enzymes, PPGK and GLKA.

Main Methods:

• Gene deletion to create glucokinase mutants (ppgK and glkA single and double mutants).
• (13)C-based metabolomic profiling to track glucose incorporation into central carbon metabolism.
• Infection models in mice to assess the role of glucokinases in Mtb establishment and persistence.

Main Results:

• Mtb possesses two functional glucokinases: polyphosphate glucokinase (PPGK) and glucokinase (GLKA).
• PPGK is essential for normal growth on glucose, while GLKA is dispensable.
• Mtb lacking both glucokinases cannot metabolize external glucose.
• Glucose phosphorylation is not required for initial infection but is critical for Mtb persistence in mouse lungs.

Conclusions:

• Mtb utilizes glucose phosphorylation, primarily via PPGK, for efficient carbon metabolism.
• Glucose is an accessible in vivo substrate for Mtb during chronic infections.
• Targeting glucose phosphorylation could be a strategy to combat persistent Mtb infections.