<unk>  is a prodrug that stops the growth of M. tuberculosis.<unk>  diffuses into the granuloma of M. tuberculosis, where the tuberculosis enzyme<unk> se converts<unk>  to the active form pyrazinoic acid. Under acidic conditions of pH 5 to 6, the pyrazinoic acid that slowly leaks out converts to the protonated conjugate acid, which is thought to diffuse easily back into the bacilli and accumulate. The net effect is that more pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH. Pyrazinoic acid was thought to inhibit the enzyme fatty acid synthase (FAS) I, which is required by the bacterium to synthesize fatty acids although this has been discounted. The accumulation of pyrazinoic acid was also suggested to disrupt membrane potential and interfere with energy production, necessary for survival of M. tuberculosis at an acidic site of infection. However, since an acidic environment is not essential for<unk>  susceptibility and<unk>  treatment does not lead to intrabacterial acidification nor rapid disruption of membrane potential, this model has also been discounted. Pyrazinoic acid was proposed to bind to the ribosomal protein S1 (RpsA) and inhibit trans-translation, but more detailed experiments have shown that it does not have this activity. The current hypothesis is that pyrazinoic acid blocks synthesis of coenzyme A. Pyrazinoic acid binds weakly to aspartate decarboxylase (PanD), triggering its degradation. This is an unusual mechanism of action in that<unk>  does not directly block the action of its target, but indirectly triggers its destruction. Resistance Mutations in the pncA gene of M. tuberculosis, which encodes a<unk> se and converts<unk>  to its active form pyrazinoic acid, are responsible for the majority of<unk>  resistance in M. tuberculosis strains. A few<unk> -resistant strains with mutations in the rpsA gene have also been identified. However, a direct association between these rpsA mutations and<unk>  resistance has not been established. The<unk> -resistant M. tuberculosis strain DHMH444, which harbors a mutation in the carboxy terminal coding region of rpsA, is fully susceptible to pyrazinoic acid and<unk>  resistance of this strain was previously associated with decreased<unk> se activity. Further, this strain was found to be susceptible to<unk>  in a mouse model of tuberculosis. Thus, current data indicate that rpsA mutations are not likely to be associated with<unk>  resistance. Currently, three main methods of testing are used for<unk>  resistance: 1) phenotypic tests where a tuberculosis strain is grown in the presence of increasing concentrations of<unk> , 2) measuring levels of<unk> se enzyme produced by the tuberculosis strain, or 3) looking for mutations in the pncA gene of tuberculosis. Concerns exist that the most widely used method for phenotypic resistance testing may overestimate the number of resistant strains. Global resistance of tuberculosis to<unk>  has been estimated to be in 16% of all cases, and 60% of people with multidrug-resistant tuberculosis.
Pyrazinamide
Safinamide
Ethambutol
Isoniazid
Oxepanoprolinamide
Rifampicin
Rifampicin/isoniazid/pyrazinamide
Rifabutin