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Antimicrobial Agents and Chemotherapy, October 2005, p. 4068-4074, Vol. 49, No. 10
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.10.4068-4074.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Molecular Characterization of Isoniazid-Resistant Mycobacterium tuberculosis Isolates Collected in Australia

Caroline Lavender,1,2 Maria Globan,2 Aina Sievers,2 Helen Billman-Jacobe,1 and Janet Fyfe2*

Department of Microbiology and Immunology, The University of Melbourne, Victoria, Australia,1 Victorian Infectious Diseases Reference Laboratory, Victoria, Australia2

Received 6 April 2005/ Returned for modification 7 May 2005/ Accepted 2 August 2005

Elucidation of the molecular basis of isoniazid (INH) resistance in Mycobacterium tuberculosis has led to the development of different genotypic approaches for the rapid detection of INH resistance in clinical isolates. Mutations in katG, in particular the S315T substitution, are responsible for INH resistance in a large proportion of tuberculosis cases. However, the frequency of the katG S315T substitution varies with population samples. In this study, 52 epidemiologically unrelated clinical INH-resistant M. tuberculosis isolates collected in Australia were screened for mutations at katG codon 315 and the fabG1-inhA regulatory region. Importantly, 52 INH-sensitive isolates, selected to reflect the geographic and genotypic diversity of the isolates, were also included for comparison. The katG S315T substitution and fabG1-inhA –15 C-to-T mutation were identified in 34 and 13 of the 52 INH-resistant isolates, respectively, and none of the INH-sensitive isolates. Three novel katG mutations, D117A, M257I, and G491C, were identified in three INH-resistant strains with a wild-type katG codon 315, fabG1-inhA regulatory region, and inhA structural gene. When analyzed for possible associations between resistance mechanisms, resistance phenotype, and genotypic groups, it was found that neither the katG S315T nor fabG1-inhA –15 C-to-T mutation clustered with any one genotypic group, but that the –15 C-to-T substitution was associated with isolates with intermediate INH resistance and isolates coresistant to ethionamide. In total, 90.4% of unrelated INH-resistant isolates could be identified by analysis of just two loci: katG315 and the fabG1-inhA regulatory region.

* Corresponding author. Mailing address: Victorian Infectious Diseases Reference Laboratory, 10 Wreckyn St., North Melbourne, Victoria, Australia 3051. Phone: 61 3 9342 2617. Fax: 61 3 9342 2666. E-mail: janet.fyfe{at}mh.org.au.

Antimicrobial Agents and Chemotherapy, October 2005, p. 4068-4074, Vol. 49, No. 10
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.10.4068-4074.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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