Sj. Cheng et al., pncA mutations as a major mechanism of pyrazinamide resistance in Mycobacterium tuberculosis: Spread of a monoresistant strain in Quebec, Canada, ANTIM AG CH, 44(3), 2000, pp. 528-532
Pyrazinamide (PZA) is an important first-line tuberculosis drug that is par
t of the currently used short-course tuberculosis chemotherapy, PZA is a pr
odrug that has to be converted to the active form pyrazinoic acid by pyrazi
namidase (PZase) activity, encoded by the pncA gene of Mycobacterium tuberc
ulosis, and loss of PZase activity is associated with PZA resistance. To fu
rther define the genetic basis of PZA resistance and determine the frequenc
y of PZA-resistant strains having pncA mutations, we sequenced the pncA gen
e from a panel of 59 PZA-resistant clinical isolates from Canada, the Unite
d States, and Korea. Two strains that did not contain pncA mutations and ha
d positive PZase turned out to be falsely resistant. Three PZase-negative s
trains (MIC, >900 mu g of PZA per ml) and one PZase-positive strain (strain
9739) (MIC, >300 mu g of PZA per ml) did not have pncA mutations, The rema
ining 53 of the 57 PZA-resistant isolates had pncA mutations, confirming th
at pncA mutation is the major mechanism of PZA resistance. Various new and
diverse mutations were found in the pncA gene. Interestingly, 20 PZA-monore
sistant 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 tha
t these strains are highly related and share almost identical IS6110 patter
ns. These data strongly suggest the spread of a PZA-monoresistant strain, w
hich has not previously been described.