Abstract
Despite significant therapeutic advances, tuberculosis (TB) remains a major global health burden, requiring prolonged multidrug therapy. Recent WHO-endorsed regimens have shortened treatment to 4 months for selected non-severe drug-sensitive pulmonary TB and introduced 6-month all-oral regimens for multidrug- and rifampicin-resistant TB.1,2 While these developments represent major progress, treatment duration remains substantially longer than that of most bacterial infections and is complicated by host-pathogen interactions that promote phenotypic drug tolerance.3,4 Persistence of Mycobacterium tuberculosis (Mtb) within macrophages and granulomas remains a major barrier to effective tuberculosis treatment. 4 While bacterial dormancy and limited drug penetration contribute to persistence, they do not fully explain the survival of metabolically active intracellular bacilli during antibiotic therapy. Emerging evidence suggests that macrophage metabolic and redox states play a critical role in shaping intracellular drug susceptibility.3,4
Macrophage metabolism as a determinant of drug tolerance
Macrophages exhibit remarkable metabolic plasticity, dynamically shifting between glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) in response to environmental cues. This metabolic state influences antimicrobial effector functions, including reactive oxygen species (ROS) production, inflammatory signaling, and phagosomal maturation. 5 Yet, until recently, the direct connection between macrophage bioenergetics and mycobacterial drug tolerance remained poorly defined.
A landmark study by Yadav et al. 6 provides compelling mechanistic insight into this link. Using a redox-sensitive Mtb biosensor, flow cytometry-based sorting, transcriptomics, and metabolic flux analysis, the authors demonstrate that macrophage bioenergetic heterogeneity generates distinct intracellular redox environments that govern Mtb drug susceptibility. 6 Macrophages with high OXPHOS and low glycolytic activity harbor reductive, drug-tolerant Mtb, whereas glycolytically active macrophages generate mitochondrial ROS largely via reverse electron transport by imposing oxidative stress that enhances antibiotic efficacy. Crucially, this work shifts the conceptual framework of TB persistence away from a binary view of replicating versus dormant bacteria. Instead, it reveals that host-controlled redox heterogeneity, even among metabolically active bacilli, is a key driver of phenotypic drug tolerance.
Nuclear factor erythroid-2 related factor-2 as a metabolic and redox checkpoint
Nuclear factor erythroid-2 related factor-2 (NRF2) is a redox-sensitive transcription factor that regulates cellular antioxidant responses and metabolic adaptation. 7 Under homeostatic conditions, NRF2 is sequestered in the cytoplasm by Kelch-like ECH-associated protein 1 (KEAP1) and targeted for proteasomal degradation. During oxidative stress, NRF2 dissociates from KEAP1, translocates to the nucleus, and activates transcription of genes involved in glutathione synthesis, mitochondrial function, and detoxification pathways. 7 In Mtb-infected macrophages, NRF2 integrates antioxidant signaling with metabolic reprogramming. Macrophages harboring reductive, drug-tolerant Mtb exhibit NRF2-driven transcriptional programs characterized by enhanced mitochondrial respiration and increased antioxidant capacity. Genetic or pharmacological attenuation of NRF2 increases mitochondrial ROS, shifts intracellular redox balance toward oxidation, and enhances antibiotic-mediated bacterial killing. 6 These findings align with prior studies implicating host redox balance and nitric oxide signaling in the control of Mtb persistence.8,9 Collectively, these observations indicate that redox regulation during tuberculosis infection is not solely a bacterial adaptation but also reflects host metabolic decisions that shape the intracellular niche.
Pharmacological reprogramming of macrophage metabolism
Perhaps the most translationally significant insight from Yadav et al. 6 is the demonstration that macrophage metabolism can be therapeutically reprogrammed using meclizine, an FDA-approved antiemetic with a long-standing safety record. Meclizine, a histamine H1 receptor antagonist widely used as an antiemetic and anti-vertigo agent, has recently emerged as a pharmacological modulator of cellular metabolism. 10 Independent of its antihistaminic activity, meclizine inhibits mitochondrial respiration and shifts macrophage bioenergetics from OXPHOS toward aerobic glycolysis. 10 In Mtb-infected macrophages, this metabolic reprogramming increases mitochondrial ROS generation, collapses bacterial redox heterogeneity, and enhances antibiotic susceptibility. 6 Importantly, preclinical studies demonstrate that adjunctive meclizine markedly reduces bacterial drug tolerance both in infected macrophages and in murine TB models without adverse pharmacokinetic interactions with frontline anti-TB drugs. 6 These findings place macrophage metabolic reprogramming firmly within the framework of host-directed therapy (HDT), an approach increasingly advocated to complement antimicrobial treatment and potentially shorten tuberculosis therapy.
Contextualizing metabolic host-directed therapy in tuberculosis
Other metabolic HDTs support the translational relevance of this approach:
✓ Metformin, an antidiabetic drug that activates AMP-activated protein kinase (AMPK), has been shown to restrict intracellular Mtb growth, enhance autophagy, and reduce inflammatory pathology. 11 A randomized controlled trial (RCT) demonstrated faster sputum culture conversion and improved clinical outcomes when metformin was used adjunctively with standard TB therapy. 12
✓ NRF2 modulators, including inhibitors such as brusatol, have been explored in experimental TB models, with NRF2 inhibition sensitizing Mtb to antibiotics by disrupting redox balance. However, NRF2 also mediates cytoprotection and tissue repair, emphasizing the need for careful therapeutic calibration. 13
✓ Metabolic pathway inhibitors, such as 2-deoxy-D-glucose (glycolysis inhibitor) and etomoxir (fatty acid oxidation inhibitor), have demonstrated efficacy in preclinical models by limiting host-derived metabolic support for intracellular bacteria. 14
Collectively, these studies establish macrophage metabolism as a clinically actionable determinant of TB drug response.
Clinical considerations and challenges
Despite strong preclinical support, several challenges must be addressed before metabolic HDTs can be widely adopted 15 :
➢ Safety: Metabolic pathways regulate essential host functions. Long-term or systemic modulation may carry risks, particularly in patients with comorbidities.
➢ Timing: Whether metabolic HDTs should be administered early to prevent tolerance or later to target persisters remains unclear.
➢ Patient heterogeneity: TB lesions and host metabolic states vary widely, suggesting that biomarker-guided patient selection may be required.
➢ Combination strategies: Metabolic HDTs will need to be integrated rationally with existing drug regimens.
In conclusion, growing evidence suggests that tuberculosis drug tolerance is not solely a bacterial phenomenon but is shaped by the metabolic and redox states of host macrophages that shape intracellular antibiotic efficacy. Recognizing macrophage metabolism as a determinant of treatment response provides a new conceptual framework for understanding persistent infection. Therapeutic strategies that target these host metabolic checkpoints may therefore complement conventional antimicrobials, enhance drug activity against intracellular bacilli, and potentially contribute to shortening tuberculosis treatment.
