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Inhibition of menaquinone biosynthesis results in re-sensitization of Bedaquiline resistant Mycobacterium tuberculosis

J Wetzel(1) B Truebody(2) A Steyn(2) P Jackson(1) D A Lamprecht(1) A Koul(1)

1:Johnson and Johnson Innovative Medicine - Global Public Health; 2:Africa Health Research Institute - University of KwaZulu Natal

Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) pose ongoing challenges to global disease control efforts. BDQ, a diarylquinoline compound, represents a significant breakthrough as the first tuberculosis medication in decades with a unique mode of action, revolutionizing MDR-TB therapy. The current MDR-TB treatment protocol involves a combination of Bedaquiline (BDQ), Pretomanid, Linezolid, and Moxifloxacin. However, the emergence of clinical resistance to BDQ has become a pressing issue, primarily due to mutations that are disrupting a drug efflux pump repressor, resulting in increased efflux of BDQ.

Mycobacterium tuberculosis relies on oxidative phosphorylation to generate ATP, crucial for both active disease and latent infection. BDQ targets ATP synthase, which results in inhibiting energy metabolism. This enzyme spans the cellular membrane, utilizing proton-motive force (PMF) generated by the electron transport chain (ETC) to produce ATP. Menaquinone facilitates electron transfer along the ETC in M. tuberculosis, connecting electron donors like NADH to acceptors. Components of this chain, including MenG, have garnered interest as potential drug targets, as seen with BDQ.

In the menaquinone biosynthesis pathway, MenG serves as one of the enzyme targets. Inhibitors of MenG demonstrate synergistic effects with TB clinical compounds, notably BDQ, validating previous studies on this enzymatic pathway. Our research presents compelling evidence that inhibiting menaquinone biosynthesis alongside BDQ treatment, effectively reverses BDQ resistance due to the drug efflux pump repressor disruption, offering a robust strategy to curb its spread in clinical settings.

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