Correlation of pncA sequence with pyrazinamide resistance level in BACTEC (TM) for 21 Mycobacterium tuberculosis clinical isolates

Mutations in the pncA gene, encoding pyrazinamidase, are considered the maj or mechanism of pyrazinamide (PZA) resistance in Mycobacterium tuberculosis , but resistant strains containing the wild-type gene have been described. The correlation of pncA sequence with PZA resistance level was examined for 21 M, tuberculosis clinical isolates, Susceptibility patterns were determi ned for 100, 300, and 900 mug/ml concentrations of the drug in BACTEC(TM), Insertions and deletions and a substitution in the putative promoter region led to high-level resistance, whereas substitutions within the open readin g frame seemed to confer variable levels of resistance. Variable resistance levels and PZase activities were also observed among isolates lacking pncA mutations. The high-level resistance (900 mug/ml) in pncA wild-type isolat es highlights the clinical significance of these isolates. These data also suggest that there may still be more than one alternative mechanism leading to PZA resistance in M. tuberculosis isolates.