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Antimicrobial Agents and Chemotherapy, August 2005, p. 3192-3197, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3192-3197.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Molecular Analysis of Cross-Resistance to Capreomycin, Kanamycin, Amikacin, and Viomycin in Mycobacterium tuberculosis

Courtney E. Maus,1,2 Bonnie B. Plikaytis,2 and Thomas M. Shinnick2*

Program in Microbiology and Molecular Genetics, Emory University, Atlanta, Georgia 30322,1 Division of Tuberculosis Elimination, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia 303332

Received 31 March 2005/ Returned for modification 16 May 2005/ Accepted 24 May 2005

Capreomycin, kanamycin, amikacin, and viomycin are drugs that are used to treat multidrug-resistant tuberculosis. Each inhibits translation, and cross-resistance to them is a concern during therapy. A recent study revealed that mutation of the tlyA gene, encoding a putative rRNA methyltransferase, confers capreomycin and viomycin resistance in Mycobacterium tuberculosis bacteria. Mutations in the 16S rRNA gene (rrs) have been associated with resistance to each of the drugs; however, reports of cross-resistance to the drugs have been variable. We investigated the role of rrs mutations in capreomycin resistance and examined the molecular basis of cross-resistance to the four drugs in M. tuberculosis laboratory-generated mutants and clinical isolates. Spontaneous mutants were generated to the drugs singularly and in combination by plating on medium containing one or two drugs. The frequencies of recovery of the mutants on single- and dual-drug plates were consistent with single-step mutations. The rrs genes of all mutants were sequenced, and the tlyA genes were sequenced for mutants selected on capreomycin, viomycin, or both; MICs of all four drugs were determined. Three rrs mutations (A1401G, C1402T, and G1484T) were found, and each was associated with a particular cross-resistance pattern. Similar mutations and cross-resistance patterns were found in drug-resistant clinical isolates. Overall, the data implicate rrs mutations as a molecular basis for resistance to each of the four drugs. Furthermore, the genotypic and phenotypic differences seen in the development of cross-resistance when M. tuberculosis bacteria were exposed to one or two drugs have implications for selection of treatment regimens.

* Corresponding author. Mailing address: Centers for Disease Control and Prevention, Mailstop G35, 1600 Clifton Road, Atlanta, GA 30333. Phone: (404) 639-1474. Fax: (404) 639-1287. E-mail: tms1{at}cdc.gov.

Antimicrobial Agents and Chemotherapy, August 2005, p. 3192-3197, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3192-3197.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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