Mycobacterial persistence- and acid-stress–related pathways

Mycobacterial persistence- and acid-stress–related pathways are a collection of adaptive mechanisms that allow Mycobacterium tuberculosis (Mtb) to survive the hostile, acidic environment of the host macrophage phagosome [1]. These pathways involve the coordinated action of the phoPR two-component system and the aprABC locus, which are essential for pH homeostasis and metabolic adaptation during infection [2][3]. A key feature of these pathways is the induction of a persistent or dormant state, where the bacteria shift their metabolism toward the glyoxylate shunt—utilizing enzymes like isocitrate lyase—to maintain viability while remaining non-replicative [4]. This metabolic flexibility contributes significantly to the drug tolerance observed in latent tuberculosis, as most conventional antibiotics target active cell wall synthesis or DNA replication [5]. Therapeutic strategies targeting these pathways include the use of pyrazinamide, which is uniquely active against Mtb in acidic environments, and bedaquiline, which inhibits the ATP synthase required for energy production in both replicating and persistent states [6].

Other names

Mtb acid-stress responseMycobacterial persistence mechanismsLatent tuberculosis infection pathwaysMtb pH homeostasis pathways

Drugs targeting these pathways typically function by disrupting pH homeostasis, inhibiting ATP synthesis, or blocking metabolic shunts required for survival in the non-replicative state.