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Title: The development of resistance to quinolones in Staphylococcus aureus
Author: Durham, Esther Jane
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2000
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In this thesis the activity of moxifloxacin, a new 8-methoxyquinolone with good activity against Gram-positive organisms, against laboratory strains and clinical isolates of S. aureus was investigated by time-kill kinetics. Mutations within gyrA and grlA did not alter the pattern of killing by moxifloxacin. To investigate the sequential development of resistance a series of low-, medium- and high-level resistant mutants were selected in a step-wise manner with moxifloxacin. The QRDRs of gyrA and grlA were characterised by DNA sequencing. Although all five first-step mutants had elevated MICs to moxifloxacin, only one was found to have a mutation in grlA. All second-step mutants were found to have a gyrA mutation, and two strains also had an inherited grlA mutation. However, the strains with two mutations did not have higher MICs of moxifloxacin than other second-step mutants. High level resistance in third-step mutants was conferred by a grlA mutations in addition to the inherited gyrA mutation. Subsequent mutant selections with ciprofloxacin gave similar results indicating DNA gyrase and not topoisomerase IV as the primary target of moxifloxacin in S. aureus. Uptake and accumulation assays did not show enhanced efflux of moxifloxacin, indicating that low-level moxifloxacin resistance in these strains is facilitated by an unknown mechanism of resistance. The activity and selection of resistance in vivo was investigated in a murine subcutaneous abscess model. Moxifloxacin was found to kill S. aureus in subcutaneous abscesses in a dose-dependent manner. In vivo mutants were selected from subcutaneous abscesses. One first step mutant had a grlA mutation; a second step mutant had a gyrA mutation but no grlA mutation. The findings of this thesis are in contrast to those of previous researchers and indicate that the development of resistance and identification of the primary target of quinolones in S. aureus may be strain, drug or method dependent and not as simple as previous research has suggested.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available