Making Mycobacterium tuberculosis killable: Operational survival phenotyping beyond the persister metaphor.

Why can genetically susceptible Mycobacterium tuberculosis (Mtb) survive months of otherwise effective chemotherapy? The persister concept gave this problem a powerful name, but its expanding use has increasingly blurred distinct causes of residual survival. Slow killing, stress-adapted physiology, residence in protective host niches, inadequate local drug exposure, and the capacity to recover after treatment can all leave viable bacilli behind, yet they do not represent the same therapeutic problem. The central challenge is therefore not simply to detect survivors, but to connect these observations across treatment and determine where irreversible killing fails. We use State-Niche-Exposure-Fate (SNEF) to make this causal chain explicit, not to replace established assays or definitions. Pyrazinamide serves as a worked model because its sterilizing activity reflects the interaction of bacterial State, lesion context, and effective Exposure rather than conventional susceptibility alone. This shifts the experimental question from whether Mtb is a "persister" to which step from susceptibility to irreversible death remains open. Closing that step may offer a more direct route to durable sterilization and shorter tuberculosis therapy.