Enhanced heterogeneity of rpoB in Mycobacterium tuberculosis found at low pH

Claire Jenkins, Joanna Bacon, Jon Allnutt, Kim A. Hatch, Alpana Bose, Denise M. O'Sullivan, Catherine Arnold, Stephen H. Gillespie, Timothy D. McHugh*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    17 Citations (Scopus)

    Abstract

    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 × 10-8 and 8.9 × 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.

    Original languageEnglish
    Pages (from-to)1118-1120
    Number of pages3
    JournalJournal of Antimicrobial Chemotherapy
    Volume63
    Issue number6
    DOIs
    Publication statusPublished - 2009

    Bibliographical note

    Funding Information:
    This project was part funded by the Peter Samuel Royal Free Fund and EU Grant EAR CPF 518152. The chemostat studies were funded by the Health Protection Agency UK.

    Keywords

    • Chemostats
    • Mutation frequencies
    • Rifampicin resistance

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