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JAC Advance Access originally published online on April 15, 2009
Journal of Antimicrobial Chemotherapy 2009 63(6):1118-1120; doi:10.1093/jac/dkp125
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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

Original research

Enhanced heterogeneity of rpoB in Mycobacterium tuberculosis found at low pH

Claire Jenkins1, Joanna Bacon2, Jon Allnutt2, Kim A. Hatch2, Alpana Bose1, Denise M. O'Sullivan1, Catherine Arnold3, Stephen H. Gillespie1,4 and Timothy D. McHugh1,*

1 University College Medical School, Royal Free Campus, London NW3 2QG, UK 2 Health Protection Agency, CEPR Porton Down, Salisbury SP4 0JG, UK 3 Health Protection Agency, Centre for Infections, London NW9 5HT, UK 4 Health Protection Agency, Holborn Gate, London, UK

Received 9 December 2008; returned 3 February 2009; revised 27 February 2009; accepted 12 March 2009

* Corresponding author. Tel: +44-20-7472-6402; E-mail: tmchugh{at}medsch.ucl.ac.uk

Objectives: The aim of this study was to gain an insight into the molecular mechanisms of the evolution of rifampicin resistance in response to controlled changes in the environment.

Methods: We determined the proportion of rpoB mutants in the chemostat culture and characterized the sequence of mutations found in the rifampicin resistance-determining region of rpoB in a steady-state chemostat at pH 7.0 and 6.2.

Results: The overall proportion of rpoB mutants of strain H37Rv remained constant for 37 days at pH 7.0, ranging between 3.6 x 10–8 and 8.9 x 10–8; however, the spectrum of mutations varied. The most commonly detected mutation, serine to leucine mutation at codon 531 (S531L), increased from 40% to 89%, while other mutations (S531W, H526Y, H526D, H526R, S522L and D516V) decreased over the 37 day sampling period. Changing the pH from 7.0 to 6.2 did not significantly alter the overall proportion of mutants, but resulted in a decrease in the percentage of strains harbouring S531L (from 89% to 50%) accompanied by an increase in the range of different mutations from 4 to 12.

Conclusions: The data confirm that the fitness of strains with the S531L mutation is greater than that of strains containing other mutations. We also conclude that at low pH the environment is permissive for a wider spectrum of mutations, which may provide opportunities for a successful mutant to survive.

Keywords: chemostats , mutation frequencies , rifampicin resistance


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