Mechanisms of Pyrazinamide Action and Resistance

Abstract

PZA is a unique anti-tuberculosis drug that plays a key role in shortening the TB therapy. PZA kills non-replicating persisters that other TB drugs fail to kill, and thus making it an essential drug for inclusion in any drug combinations for treating drug susceptible and drug-resistant TB such as MDR-TB. PZA acts differently from common antibiotics by inhibiting multiple targets such as energy production, trans-translation and perhaps pantothenate /coenzyme A required for persister survival. Resistance to PZA is mostly caused by mutations in the pncA gene encoding pyrazinamidase involved in conversion of the prodrug PZA to the active form POA. Mutations in the drug target RpsA are also found in some PZA-resistant strains. The recent finding that panD mutations are found in some PZA-resistant strains without pncA or rpsA mutations may suggest a third PZA resistance gene and a potential new target of PZA. Current phenotype based PZA susceptibility testing is not reliable due to false resistance, and sequencing of the pncA gene represents a more rapid, cost-effective and more reliable molecular test for PZA susceptibility testing and should be used for guiding improved treatment of MDR/XDR-TB. Finally, the story of PZA has important implications for not only TB therapy but also chemotherapy in general. PZA serves as a model prototype persister drug and hopefully a ‘tipping point’ that inspires new efforts at developing a new type of antibiotics or drugs that target non-replicating persisters for improved treatment of not only TB but also other persistent bacterial infections.

Improved Detection by Next-Generation Sequencing of Pyrazinamide Resistance in Mycobacterium tuberculosis Isolates

“…The panD gene encodes an aspartate decarboxylase involved in synthesis of ␤-alanine, a precursor of pantothenate and coenzyme A (18). Three isolates carried mutations in the pncA gene promoter region (T Ϫ10 C and T Ϫ12 C), and double mutations were noticed in three isolates.…”

“…Also, recently, two new genes (RpsA and panD) that might be implicated in PZA resistance have been identified (16)(17)(18). The RpsA gene codes for a vital ribosomal protein involved in trans-translation (16)(17)(18). Trans-translation is involved in degradation of potentially toxic …”

Lung Tissue Concentrations of Pyrazinamide among Patients with Drug-Resistant Pulmonary Tuberculosis

“…Pyrazinamide is converted into its active moiety, pyrazinoic acid (POA), within Mycobacterium tuberculosis, and a low pH outside the mycobacteria favors the accumulation of POA within the mycobacteria, leading to cell death. Thus, lesion pH measurements are essential to understanding the role of prolonged pyrazinamide use in patients with chronic pulmonary disease (12). To evaluate the target site concentrations of pyrazinamide, we utilized the technique of microdialysis (D), which allows the measurement of unbound (pharmacologically active) extracellular drug concentrations at the site of disease.…”

Identification of Novel Efflux Proteins Rv0191, Rv3756c, Rv3008, and Rv1667c Involved in Pyrazinamide Resistance in Mycobacterium tuberculosis

“…The number of new cases of multidrug-resistant tuberculosis (MDR-TB) has reached 480,000. PZA is an important TB drug that shortens the duration of therapy from the previous 9 to 12 months to 6 months (2) due to its ability to kill a population of persister bacilli that are not killed by other TB drugs (3,4). However, clinically, resistance to PZA is becoming an increasing problem (5)(6)(7)(8), and its mechanisms of resistance are not completely understood.…”