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Title: Evolution of the mechanisms of drug resistance in Mycobacterium tuberculosis
Author: O'Sullivan, Denise Mary
ISNI:       0000 0001 3454 4346
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2007
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The aim of this thesis was to investigate the mechanisms by which Mycobacterium tuberculosis develops resistance. Resistance depends entirely on genetic alterations within the genome as a consequence of spontaneous mutations. It is hypothesized that an isoniazid resistant strain, deficient in its response to oxidative damage through a mutation in katG, demonstrates a hypermutator phenotype which leads to multiple drug resistance. However there was no evidence of an increased mutation rate. It is likely that compensatory mutations are occurring allowing the bacteria to adapt to its surroundings. The hypothesis that oxidative damage is the major force driving mutations in M. tuberculosis was tested by analyzing reported mutations in rpoB and pncA. The lack of evidence of this type of damage indicates that M. tuberculosis is sufficiently competent in repair. This leads to the conclusion that oxidative damage is not the primary mechanism for mutation in the M. tuberculosis genome and instead it is the relative fitness of the mutant strain coupled with the resistance phenotype that fixes mutations and permits survival and detection. Sub-optimal therapy can lead to the selection of mutant strains. It has been shown previously that exposure to sub-inhibitory concentrations of quinolone can increase the mutation rate of mycobacteria. Gene expression profiling was used to determine whether this increase in mutation rate was due to an induction of the SOS repair genes among other DNA repair systems and found that some of these genes were differentially expressed during treatment. Sub-populations of resistant bacteria may exist in clinical specimens prior to drug exposure and this population may be likely to pre-dominate leading to heterogeneous resistance. This phenomenon called heteroresistance was demonstrated in laboratory strains of Mycobacterium fortuitum and Mycobacterium smegmatis and in M. fortuitum clinical isolates.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available