Affiliation:
1. Department of Molecular Microbiology and Immunology, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 212051;
2. Laboratoire de Sante Publique du Quebec, Sainte-Anne-de-Bellevue, Canada2; and
3. National Jewish Medical and Research Center, Denver, Colorado 802063
Abstract
ABSTRACT
Pyrazinamide (PZA) is an important first-line tuberculosis drug that is part of the currently used short-course tuberculosis chemotherapy. PZA is a prodrug that has to be converted to the active form pyrazinoic acid by pyrazinamidase (PZase) activity, encoded by the
pncA
gene of
Mycobacterium tuberculosis
, and loss of PZase activity is associated with PZA resistance. To further define the genetic basis of PZA resistance and determine the frequency of PZA-resistant strains having
pncA
mutations, we sequenced the
pncA
gene from a panel of 59 PZA-resistant clinical isolates from Canada, the United States, and Korea. Two strains that did not contain
pncA
mutations and had positive PZase turned out to be falsely resistant. Three PZase-negative strains (MIC, >900 μg of PZA per ml) and one PZase-positive strain (strain 9739) (MIC, >300 μg of PZA per ml) did not have
pncA
mutations. The remaining 53 of the 57 PZA-resistant isolates had
pncA
mutations, confirming that
pncA
mutation is the major mechanism of PZA resistance. Various new and diverse mutations were found in the
pncA
gene. Interestingly, 20 PZA-monoresistant strains and 1 multidrug-resistant isolate from Quebec, Canada, all had the same
pncA
mutation profile, consisting of an 8-nucleotide deletion and an amino acid substitution of Arg140→Ser. Strain typing indicated that these strains are highly related and share almost identical IS
6110
patterns. These data strongly suggest the spread of a PZA-monoresistant strain, which has not previously been described.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
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