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  • Title: New mutations in pncA of in vitro selected pyrazinamide-resistant strains of Mycobacterium tuberculosis.
    Author: Bamaga M, Zhang H, Wright DJ.
    Journal: Microb Drug Resist; 2001; 7(3):223-8. PubMed ID: 11759083.
    Abstract:
    Mutations within the pncA gene can cause pyrazinamide (PZA) resistance in Mycobacterium tuberculosis. To study further the mutational events leading to PZA resistance, a H37Rv PZA-susceptible strain was used to derive PZA-resistant mutants in vitro. This parental strain was grown at gradually increased concentrations of PZA (from 200 up to 500 microg/ml). A total of eight variant strains were selected for further study. PZA resistance was selected at 250 microg/ml or higher. Seven of them lost PZase activity and hence were PZA resistant. The remaining strain has shown a functional PZase and hence was sensitive to PZA after being exposed to 200 microg/ml PZA. Sequence analysis shows different novel mutations within the pncA gene of these variants. Two silent mutations at nucleotide 6 (G --> A) and 300 (C --> T) were found in the PZA-sensitive variant. Among the seven PZA-resistant variants, there were three deletion mutations found at nucleotide 78 (G), 79 (A), and 143 (A), all resulting in a frameshift, and one nonsense mutation at nucleotide 102 (C --> G), creating a stop codon TAG. It was observed that the mutations found in the pncA gene of these PZA-resistant mutants show a distinctive pattern: mutation positions moved toward the beginning of the open reading frame correlating with the increase in PZA concentration, suggesting a possible relationship between the increase of PZA concentration and the early occurrence of mutations on the pncA gene.
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