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JAC Advance Access originally published online on July 4, 2009
Journal of Antimicrobial Chemotherapy 2009 64(3):515-523; doi:10.1093/jac/dkp237
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
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Original research

Resistant mutants of Mycobacterium tuberculosis selected in vitro do not reflect the in vivo mechanism of isoniazid resistance

Indra L. Bergval*, Anja R. J. Schuitema, Paul R. Klatser and Richard M. Anthony

KIT Biomedical Research, Royal Tropical Institute, Amsterdam, The Netherlands

Received 5 March 2009; returned 21 April 2009; revised 11 May 2009; accepted 11 June 2009

* Corresponding author. Tel: +31-(0)20-5665448; Fax: +31-(0)20-6971841; E-mail: i.bergval{at}kit.nl

Objectives: The high prevalence of isoniazid-resistant Mycobacterium tuberculosis is often explained by a high mutation rate for this trait, although detailed information to support this theory is absent. We studied the development of isoniazid resistance in vitro, making use of a laboratory strain of M. tuberculosis.

Methods: Spontaneous isoniazid-resistant mutants were characterized by molecular methods allowing identification of the most commonly encountered resistance-conferring mutations. Additionally, we determined the in vitro mutation rates for isoniazid and rifampicin resistance, and characterized the genome of a triple-resistant strain.

Results: Results confirm that the in vitro mutation rate for isoniazid resistance (3.2 x 10–7 mutations/cell division) is much higher than the rate for rifampicin resistance (9.8 x 10–9 mutations/cell division). However, in the majority of the in vitro mutants katG was partially or completely deleted and neither of the two most common in vivo mutations, katG-S315T or inhA-C(-)15T, were found in 120 isogenic mutants. This implies that clinically prevalent resistance mutations were present in <0.8% of isoniazid-resistant strains selected in vitro (95% CI 0%–2.5%). The triple-resistant strain had acquired isoniazid resistance via a 49 kbp deletion, which included katG. Apart from previously identified resistance-conferring mutations, three additional point mutations were acquired during sequential selection steps.

Conclusions: These outcomes demonstrate that the in vivo mechanism of isoniazid resistance is not reflected by in vitro experiments. We therefore conclude that the high in vitro mutation rate for isoniazid resistance is not a satisfactory explanation for the fact that isoniazid monoresistance is significantly more widespread than monoresistance to rifampicin.

Keywords: tuberculosis , drug resistance , mutation rate


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