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Antimicrobial Agents and Chemotherapy, December 2000, p. 3298-3301, Vol. 44, No. 12
0066-4804/00/$04.00+0

Characterization of Spontaneous, In Vitro-Selected, Rifampin-Resistant Mutants of Mycobacterium tuberculosis Strain H37Rv

Glenn P. Morlock, Bonnie B. Plikaytis, and Jack T. Crawford*

National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia

Received 26 April 2000/Returned for modification 18 May 2000/Accepted 28 August 2000

Resistance to rifampin in Mycobacterium tuberculosis results from mutations in the gene coding for the beta subunit of RNA polymerase (rpoB). At least 95% of rifampin-resistant isolates have mutations in rpoB, and the mutations are clustered in a small region. About 40 distinct point mutations and in-frame insertions and deletions in rpoB have been identified, but point mutations in two codons, those coding for Ser531 and His526, are seen in about 70% of rifampin-resistant clinical isolates, with Ser531-to-Leu (TCG-to-TGG) mutations being by far the most common. To explore this phenomenon, we isolated independent, spontaneous, rifampin-resistant mutant versions of well-characterized M. tuberculosis laboratory strain H37Rv by plating 100 separate cultures, derived from a single low-density inoculum, onto rifampin-containing medium. Rifampin-resistant mutants were obtained from 64 of these cultures. Although we anticipated that the various point mutations would occur with approximately equal frequencies, sequencing the rpoB gene from one colony per plate revealed that 39 (60.9%) were Ser531 to Leu. We conclude that, for unknown reasons, the associated rpoB mutation occurs at a substantially higher rate than other rpoB mutations. This higher mutation rate may contribute to the high percentage of this mutation seen in clinical isolates.

* Corresponding author. Mailing address: Tuberculosis/Mycobacteriology Branch, Mailstop F-08, Centers for Disease Control and Prevention, 1600 Clifton Rd., N.E., Atlanta, GA 30333. Phone: (404) 639-1280. Fax: (404) 639-1287. E-mail: jcrawford{at}cdc.gov.

Antimicrobial Agents and Chemotherapy, December 2000, p. 3298-3301, Vol. 44, No. 12
0066-4804/00/$04.00+0


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