Vitamin B6 biosynthesis is essential for survival and virulence of Mycobacterium tuberculosis

Area of Science:

• Microbiology
• Biochemistry
• Drug Discovery

Background:

• Multidrug-resistant tuberculosis (MDR-TB) poses a significant global health threat, necessitating novel therapeutic targets.
• Essential cofactor biosynthesis pathways, absent in humans, are attractive targets for antimycobacterial drug development.
• Pyridoxal 5-phosphate (PLP), the active form of vitamin B6, is a crucial cofactor for numerous metabolic processes.

Purpose of the Study:

• To investigate the role of vitamin B6 biosynthesis in the survival and virulence of Mycobacterium tuberculosis (M. tuberculosis).
• To evaluate the potential of the PLP synthase pathway as a target for novel antitubercular agents.

Main Methods:

• Genetic disruption of the pdx1 gene to create a vitamin B6 auxotrophic M. tuberculosis mutant (Δpdx1).
• Assessment of mutant growth and survival under various conditions, including nutrient limitation and oxygen depletion (dormancy model).
• Evaluation of mutant virulence in an immunocompetent mouse model of tuberculosis infection.

Main Results:

• Disruption of pdx1 rendered M. tuberculosis strictly auxotrophic for vitamin B6, confirming the essentiality of de novo PLP biosynthesis.
• The Δpdx1 mutant exhibited impaired growth and survival in vitro and failed to persist or regrow effectively in a mouse model.
• PLP biosynthesis was critical for M. tuberculosis regrowth following oxygen exposure in a dormancy model.

Conclusions:

• Vitamin B6 biosynthesis is indispensable for the survival and virulence of M. tuberculosis in vivo.
• The PLP synthase pathway represents a promising candidate target for the development of new antitubercular drugs.
• Inhibition of vitamin B6 synthesis could offer a novel strategy to combat MDR-TB.