Derailing the aspartate pathway of Mycobacterium tuberculosis to eradicate persistent infection

Area of Science:

• Microbiology
• Metabolic Biochemistry
• Drug Discovery

Background:

• Developing new anti-tuberculosis drugs is hindered by a lack of validated targets for persistent infections.
• Mycobacterium tuberculosis (Mtb) persistence relies on specific metabolic vulnerabilities.
• The aspartate pathway is a critical metabolic route in Mtb.

Purpose of the Study:

• To identify and validate novel drug targets within the Mtb metabolic network.
• To investigate the role of the aspartate pathway in Mtb persistence.
• To evaluate the therapeutic potential of inhibiting the aspartate pathway against chronic tuberculosis.

Main Methods:

• Combinatorial metabolomic and transcriptomic analysis of Mtb.
• Investigation of threonine and homoserine auxotrophs.
• Enzyme inhibition assays targeting aspartate pathway branch-point enzymes.
• Assessment of chronic infection clearance in vivo.

Main Results:

• The aspartate pathway is essential for Mtb persistence.
• Inhibition of threonine biosynthesis leads to metabolic dysregulation, including lysine and diaminopimelic acid (DAP) accumulation.
• Mtb employs adaptive mechanisms like lysine export and aminoadipate catabolism to manage metabolic stress.
• Targeting aspartate pathway enzymes effectively clears chronic Mtb infections.

Conclusions:

• The aspartate pathway is a crucial, yet vulnerable, metabolic network in Mtb.
• Mtb utilizes complex metabolic control mechanisms to maintain persistence.
• The aspartate pathway represents a promising target space for novel anti-tuberculosis drug development.