Metabolic Pathways in Mycobacterium tuberculosis

Mycobacterium tuberculosis exhibits a highly flexible and robust metabolic network that underpins its capacity to survive diverse environmental stresses and to establish both acute and chronic infections. Central carbon metabolism integrates multiple nutrient sources—including fatty acids, carbohydrates and amino acids—through the tricarboxylic acid (TCA) cycle, gluconeogenesis and anaplerotic reactions. The bacterium’s glyoxylate shunt and methylcitrate cycle enable the utilisation of host-derived lipids and odd-chain fatty acids, while specialised nodes such as phosphoenolpyruvate carboxykinase and fructose-1,6-bisphosphate aldolase coordinate the interface between gluconeogenesis and glycolysis. Concurrently, cofactor homeostasis, particularly of NAD(H) and NADP(H), orchestrates redox balance and respiratory activity. Adaptations in trehalose metabolism and amino acid pathways further support energy production, cell-wall biosynthesis and persistence under antibiotic pressure. The interplay of these pathways not only confers metabolic plasticity but also reveals multiple potential targets for therapeutic intervention aimed at eradicating both actively replicating bacilli and drug-tolerant persister populations.

Research from Nature Portfolio

Recent studies have demonstrated that adaptation of trehalose metabolism is central to both transient antibiotic tolerance and permanent drug resistance. Persister-like bacilli remodel trehalose utilisation to sustain ATP production and antioxidant defence, diverting trehalose from cell-surface glycolipids into central carbon intermediates. Inhibition of key trehalose-processing enzymes restores antibiotic susceptibility in multidrug-resistant strains, highlighting a potential adjunctive therapeutic strategy. Complementary work has uncovered metabolic redundancy in gluconeogenesis: aside from the canonical fructose 1,6-bisphosphatase (FBPase), an alternative enzyme maintains fructose-6-phosphate production when the primary FBPase is absent. Only dual disruption of both enzymes abolishes gluconeogenesis and attenuates virulence in a murine model, affirming the essentiality of this pathway. Further investigation of amino-acid biosynthesis has identified the aspartate pathway as a vulnerable node in persistent infections. Threonine and homoserine auxotrophs exhibit rapid cell death, and blockage of upstream aspartate kinase triggers flux imbalances that cannot be compensated by export or catabolism of accumulating intermediates, leading to clearance of chronic infection. These findings collectively emphasise the importance of metabolic control points in M. tuberculosis persistence and pathogenesis.

Metabolic Pathways in Mycobacterium tuberculosis publication trend

The graph below shows the total number of articles in metabolic pathways in mycobacterium tuberculosis across all publications each year (not limited to Nature Index journals).

Technical terms

TCA cycle: A sequence of enzymatic reactions that oxidise acetyl-CoA to CO₂, generating reducing equivalents for respiration.

Glyoxylate shunt: A bypass of the TCA cycle that conserves carbon by converting isocitrate to glyoxylate and succinate, enabling growth on fatty acids.

Gluconeogenesis: The synthesis of glucose and other carbohydrates from non-carbohydrate precursors, critical for biomass production during host infection.

Anaplerotic reaction: A process that replenishes TCA cycle intermediates, such as the carboxylation of phosphoenolpyruvate to oxaloacetate.

Trehalose: A disaccharide of glucose that serves both structural and energy-storage functions, modulating stress responses and cell-wall biosynthesis.

References

1. Transient drug-tolerance and permanent drug-resistance rely on the trehalose-catalytic shift in Mycobacterium tuberculosis. Nature Communications (2019).
2. Two enzymes with redundant fructose bisphosphatase activity sustain gluconeogenesis and virulence in Mycobacterium tuberculosis. Nature Communications (2015).
3. Derailing the aspartate pathway of Mycobacterium tuberculosis to eradicate persistent infection. Nature Communications (2019).
4. One‐shot 13C15N‐metabolic flux analysis for simultaneous quantification of carbon and nitrogen flux. Molecular Systems Biology (2023).
5. Metabolically distinct roles of NAD synthetase and NAD kinase define the essentiality of NAD and NADP in Mycobacterium tuberculosis. mBio (2023).