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Acquisition of rifabutin resistance by a rifampicin resistant mutant of Mycobacterium tuberculosis involves an unusual spectrum of mutations and elevated frequency : research


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Abstract: Mutations in a small region of the rpoB gene are responsible for most rifamycin resistance in Mycobacterium tuberculosis. In this study we have sequentially generated resistant strains to first rifampicin and then rifabutin. Portions of the rpoB gene were sequenced from 131 randomly selected mutants. Second round selection resulted in a changed frequency of specific mutations. Mycobacterium tuberculosis (strain Mtb72) rifamycin resistant mutants were selected in vitro with either rifampicin or rifabutin. One mutant R190 (rpoB S522L) selected with rifampicin had a rifampicin MIC of 32 μg/ml but remained sensitive to rifabutin (MIC<0.8 μg/ml). This mutant was subjected to a second round of selection with rifabutin. All 105 first round resistant mutants derived from the parent strain (Mtb72) screened acquired mutations within the 81 bp rpoB hotspot. When the rifampicin resistant but rifabutin sensitive S522L mutant was subjected to a second round of selection, single additional rpoB mutations were identified in 24 (92%) of 26 second round mutants studied, but 14 (54%) of these strains contained mutations outside the 81 bp hotspot (codons 144, 146, 148, 505). Additionally, spontaneous rifabutin resistant mutants were produced at >10 times the frequency by the S522L mutant than the parent strain. First round selection of mutation S522L with rifampicin increased the frequency and changed the spectrum of mutations identified after selection with rifabutin. Further studies should include generating mutants to other antimicrobials and measuring mutation rates, allowing the contribution of each of these possible explanations to be explored. The details of how resistance mutations arise would be valuable when formulating standard treatment regimens with the aim of minimising the emergence of resistance in treated populations.
Authors: Anthony, R.M. , Schuitema, A.R.J. , Bergval, I.L. , Brown, T.J. , Oskam, L. , Klatser, P.R.
Category: Research
ISSN: 1476-0711
Volume: 4
Journal: Annals of Clinical Microbiology and Antimicrobials
Keywords: health , disease prevention and control
Language: eng
Organization: KIT - Royal Tropical Institute
PAGE: 6
Year: 2005
Right: © 2005 Anthony et al. This work is licensed under a Creative Commons Attribution License.
Subject: Health and Nutrition
Title: Acquisition of rifabutin resistance by a rifampicin resistant mutant of Mycobacterium tuberculosis involves an unusual spectrum of mutations and elevated frequency : research