Inhibiting the stringent response blocks Mycobacterium tuberculosis entry into quiescence and reduces persistence

Area of Science:

• Microbiology
• Molecular Biology
• Drug Discovery

Background:

• The stringent response is crucial for Mycobacterium tuberculosis (Mtb) survival under stress.
• RelMtb is the key enzyme mediating the stringent response in Mtb.

Purpose of the Study:

• To investigate the role of RelMtb in Mtb's response to nutrient starvation.
• To identify inhibitors of RelMtb for potential therapeutic applications against Mtb persisters.

Main Methods:

• Generating a relMtb-deficient Mtb strain.
• Performing metabolomics analysis on starved and nutrient-rich Mtb cultures.
• Screening a large pharmaceutical library for RelMtb inhibitors.
• Evaluating the efficacy of identified inhibitors alone and in combination with isoniazid.

Main Results:

• Mtb lacking RelMtb failed to slow replication and metabolism during nutrient starvation, indicating an inability to enter quiescence.
• The relMtb-deficient strain showed increased susceptibility to isoniazid during starvation and in a mouse infection model.
• A novel compound, X9, was identified as a direct inhibitor of RelMtb, killing starved Mtb and potentiating isoniazid's activity.

Conclusions:

• RelMtb is essential for Mtb to enter a quiescent state during nutrient starvation.
• Inhibiting RelMtb represents a promising strategy to eliminate Mtb persisters.
• Targeting RelMtb could lead to shorter and more effective tuberculosis treatments.