JAC Advance Access published online on June 24, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn259
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Original research |
The effect of oxidative stress on the mutation rate of Mycobacterium tuberculosis with impaired catalase/peroxidase function
1 Centre for Medical Microbiology, Department of Infection, Hampstead Campus, University College London, Rowland Hill Street, Hampstead, London NW3 2PF, UK 2 Health Protection Agency, Regional Microbiology Network, Holborn Gate, London WC1V 7PP, UK
Received 20 December 2007; returned 9 April 2008; revised 13 May 2008; accepted 2 June 2008
* Correspondence address. Department of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK. Tel: +44-20-7927-2468; Fax: +44-20-7637-4314; E-mail: denise.o'sullivan{at}lshtm.ac.uk
Objectives: To determine the effect of oxidative stress on isoniazid-resistant Mycobacterium tuberculosis deficient in catalase/peroxidase activity to varying degrees through mutation in katG.
Methods: The mutation rate was determined for a set of isogenic strains with different katG alleles giving different catalase and/or peroxidase activities following exposure to the oxidizing agent, hydrogen peroxide. Mutants were selected on rifampicin, and the location and nature of the mutation were identified by sequencing the rpoB gene.
Results: No evidence was found to suggest that strains that had impaired catalase/peroxidase activity were hypermutable, and the presence of excess hydrogen peroxide had no effect on the mutation rate. An unusual pattern of mutations in rpoB was observed in catalase-deficient strains with only 3 of 66 having mutations within the rifampicin resistance-determining region.
Conclusions: The mutation rate of M. tuberculosis in response to oxidative stress is not increased in strains with significant deficits in catalase and peroxidase activity. Our data suggest that isoniazid-resistant strains compensate for their reduced ability to detoxify oxidative stress effectively. Interestingly, mutations were found in unusual locations at positions similar to those found in clinical isoniazid-resistant strains.
Key Words: oxidative stress response , isoniazid , M. tuberculosis
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