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Antimicrobial Agents and Chemotherapy, February 2005, p. 571-577, Vol. 49, No. 2
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.2.571-577.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Mutation of tlyA Confers Capreomycin Resistance in Mycobacterium tuberculosis

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

Program in Microbiology and Molecular Genetics, Emory University,1 Division of TB Elimination, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia2

Received 22 July 2004/ Returned for modification 10 September 2004/ Accepted 8 October 2004

Capreomycin, an important drug for the treatment of multidrug-resistant tuberculosis, is a macrocyclic peptide antibiotic produced by Saccharothrix mutabolis subspecies capreolus. The basis of resistance to this drug was investigated by isolating and characterizing capreomycin-resistant strains of Mycobacterium smegmatis and Mycobacterium tuberculosis. Colonies resistant to capreomycin were recovered from a library of transposon-mutagenized M. smegmatis. The transposon insertion site of one mutant was mapped to an open reading frame in the unfinished M. smegmatis genome corresponding to the tlyA gene (Rv1694) in the M. tuberculosis H37Rv genome. In M. smegmatis spontaneous capreomycin-resistant mutants, the tlyA gene was disrupted by one of three different naturally occurring insertion elements. Genomic DNAs from pools of transposon mutants of M. tuberculosis H37Rv were screened by PCR by using primers to the tlyA gene and the transposon to detect mutants with an insertion in the tlyA gene. One capreomycin-resistant mutant was recovered that contained the transposon inserted at base 644 of the tlyA gene. Complementation with the wild-type tlyA gene restored susceptibility to capreomycin in the M. smegmatis and M. tuberculosis tlyA transposon mutants. Mutations were found in the tlyA genes of 28 spontaneous capreomycin-resistant mutants generated from three different M. tuberculosis strains and in the tlyA genes of capreomycin-resistant clinical isolates. In in vitro transcription-translation assays, ribosomes from tlyA mutant but not tlyA+ strains resist capreomycin inhibition of transcription-translation. Therefore, TlyA appears to affect the ribosome, and mutation of tlyA confers capreomycin resistance.

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

Antimicrobial Agents and Chemotherapy, February 2005, p. 571-577, Vol. 49, No. 2
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.2.571-577.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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