An exacerbated phosphate starvation response triggers Mycobacterium tuberculosis glycerol utilization at acidic pH

Area of Science:

• Microbiology
• Molecular Biology
• Infectious Diseases

Background:

• Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a leading global infectious disease.
• Macrophages use phagosome acidification to restrict intracellular bacterial growth, a process Mtb adapts to via 'acid growth arrest' at pH <5.8.
• Understanding Mtb's survival mechanisms within the host is crucial for developing new anti-TB strategies.

Purpose of the Study:

• To identify genes influencing Mtb fitness during acid growth arrest.
• To elucidate the role of inorganic phosphate (Pi) metabolism in Mtb's acid stress response.
• To uncover novel pathways for therapeutic intervention against Mtb.

Main Methods:

• Conducted a genome-wide mutagenesis screen to identify Mtb genes affecting fitness during acid growth arrest.
• Investigated the function of the inorganic phosphate (Pi) uptake system (Pst-1) and its regulator, RegX3.
• Assessed the impact of gene deletions and overexpression on Mtb growth in acidic conditions.

Main Results:

• Identified 95 genes affecting Mtb fitness during acid growth arrest.
• Demonstrated that the Pst-1 system regulates Mtb's ability to replicate in acidic environments.
• Showed that deleting pstA1 leads to RegX3 overexpression, restoring Mtb growth in acid, and implicated limited glycerol uptake and ROS-mediated GAPDH inhibition.

Conclusions:

• The inorganic phosphate (Pi) starvation response unexpectedly regulates Mtb's acid growth arrest.
• RegX3 overexpression can restore Mtb growth in acidic conditions, highlighting its potential as a therapeutic target.
• This study deepens the understanding of Mtb's adaptation to host environments, including redox homeostasis and nutrient utilization.