Menaquinone depletion resensitises bedaquiline-resistant tuberculosis

Area of Science:

• Microbiology
• Drug Discovery
• Molecular Biology

Background:

• Tuberculosis (TB) is a major global health threat.
• Rising resistance to bedaquiline, a key TB drug, compromises treatment efficacy.
• Bedaquiline resistance often stems from mutations in Rv0678, increasing drug efflux.

Purpose of the Study:

• To identify novel targets to overcome bedaquiline resistance in Mycobacterium tuberculosis.
• To develop potent inhibitors of menaquinone biosynthesis to restore drug susceptibility.
• To evaluate the efficacy of targeting menaquinone pathway enzymes in vivo.

Main Methods:

• Chemical optimization of inhibitors targeting the MenG enzyme.
• In vitro assessment of bactericidal activity and restoration of bedaquiline susceptibility.
• In vivo efficacy studies of combination therapy in a mouse model of tuberculosis.

Main Results:

• Identification of potent bactericidal inhibitors of MenG with in vivo efficacy.
• MenG inhibition restored bedaquiline susceptibility in resistant Mycobacterium tuberculosis strains.
• Combination therapy with MenG inhibitors and bedaquiline achieved significant bacterial burden reduction.

Conclusions:

• Targeting menaquinone biosynthesis, specifically MenG, is a viable strategy to combat bedaquiline-resistant tuberculosis.
• Inhibition of MenG and related pathway enzymes can resensitize resistant strains to existing drugs.
• This approach offers a novel therapeutic strategy to strengthen future tuberculosis treatment regimens.