Bedaquiline reprograms central metabolism to reveal glycolytic vulnerability in Mycobacterium tuberculosis

Abstract

The approval of bedaquiline (BDQ) for the treatment of tuberculosis has generated substantial interest in inhibiting energy metabolism as a therapeutic paradigm. However, it is not known precisely how BDQ triggers cell death in Mycobacterium tuberculosis (Mtb). Using 13C isotopomer analysis, we show that BDQ-treated Mtb redirects central carbon metabolism to induce a metabolically vulnerable state susceptible to genetic disruption of glycolysis and gluconeogenesis. Metabolic flux profiles indicate that BDQ-treated Mtb is dependent on glycolysis for ATP production, operates a bifurcated TCA cycle by increasing flux through the glyoxylate shunt, and requires enzymes of the anaplerotic node and methylcitrate cycle. Targeting oxidative phosphorylation (OXPHOS) with BDQ and simultaneously inhibiting substrate level phosphorylation via genetic disruption of glycolysis leads to rapid sterilization. Our findings provide insight into the metabolic mechanism of BDQ-induced cell death and establish a paradigm for the development of combination therapies that target OXPHOS and glycolysis.

Mycobacterium tuberculosis DosS binds H2S through its Fe3+ heme iron to regulate the Dos dormancy regulon

“…6 and ( 7)). These findings suggest that inhibition of respiration (or hypoxia) is not the sole factor that induces the Dos dormancy regulon, and are consistent with the action of the TB drug bedaquiline, which also stimulates respiration (56) and induces the Dos dormancy regulon (57).…”

Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis

“…This would be consistent with our previous data demonstrating propionate vulnerability of strains lacking Rv1127c that could be complemented by vitamin B12 to activate the methylmalonyl pathway. The precise function of Rv1127c may have therapeutic implications as ΔRv1127c is attenuated for intracellular survival and is more sensitive to the antibiotic bedaquiline (Mackenzie et al, 2020). Rv1127c is thereby an attractive target for developing anti‐TB drugs which synergise with bedaquiline, a critical drug in the new shortened therapy against drug‐resistant TB.…”

A competitive activity-based protein profiling platform yields cell wall synthesis inhibitors active against replicating and non-replicatingMycobacterium tuberculosis

“…Pretomanid acts in replicating Mtb by inhibiting the biosynthesis of essential mycolic acids. Although bedaquiline is an ATP-synthesis inhibitor, we and others have shown that the resulting downstream metabolic perturbation produces morphological changes that resemble those from cell-wall acting inhibitors (Mackenzie et al, 2020;Smith et al, 2020).…”