Gallein potentiates isoniazid's ability to suppress Mycobacterium tuberculosis growth

Area of Science:

• Microbiology
• Molecular Biology
• Drug Discovery

Background:

• Tuberculosis (TB) treatment is challenging due to drug tolerance in Mycobacterium tuberculosis (Mtb).
• Polyphosphate (polyP) accumulation in Mtb enhances antibiotic tolerance, and in Neisseria gonorrhoeae, it potentiates antimicrobial resistance.
• The mechanism of bacterial adaptation to antimicrobial pressure via polyP is not fully understood.

Purpose of the Study:

• To investigate the role of polyphosphate (polyP) in Mycobacterium tuberculosis (Mtb) adaptation to isoniazid (INH).
• To evaluate the potential of gallein, a polyphosphate kinase inhibitor, in combination therapy against Mtb.

Main Methods:

• Monitoring polyP levels (cellular, extracellular, cell surface) in Mtb exposed to INH.
• Assessing the effect of gallein on INH-induced polyP accumulation.
• Evaluating the synergistic effect of gallein and INH on Mtb growth in vitro and within human macrophages.
• Analyzing the impact of INH and gallein on Mtb cell envelope formation and metabolite levels via metabolomics.

Main Results:

• Mtb enhances polyP accumulation (cellular, extracellular, cell surface) in response to INH.
• Gallein inhibits INH-induced increases in extracellular and cell surface polyP.
• Gallein and INH exhibit synergistic activity, reducing Mtb growth in vitro and in macrophages.
• Combined INH and gallein treatment inhibits Mtb cell envelope formation and significantly alters metabolite levels, particularly those involved in cell envelope synthesis.

Conclusions:

• Mtb utilizes polyP accumulation as an adaptive mechanism to tolerate isoniazid.
• Gallein effectively blocks this polyP-mediated adaptation.
• The combination of gallein and INH demonstrates synergistic efficacy against Mtb, suggesting a promising therapeutic strategy for TB treatment.