Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.649652
Title: The impact of target site alterations to fluoroquinolones in Streptococcus pneumoniae
Author: Dorai-Schneiders, Thamarai
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2001
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Abstract:
Thirty-one clinical pneumococcal isolates that exhibited decreased sensitivity to the fluoroquinolones were found to express a combination of resistance mechanisms. Efflux inhibition studies have shown that all the selected pneumococcal isolates demonstrated a reduction to ciprofloxacin and norfloxacin in the presence of reserpine (efflux pump inhibitor). No such effect was observed with either of the extended spectrum quinolones (moxifloxacin and gatifloxacin) tested. Sequencing analysis of 11 representative isolates revealed that none of the organisms sustained a genetic mutation in either gyrA or parC except two strains 7368 which demonstrated a Lysine137 (r)Asn change and BPL27 which has a Asp87 (r)Asn mutation. Both these strains exhibited a MIC of 4mg/l to ciprofloxacin but remained sensitive to moxifloxacin. Other isolates that exhibited identical MICs were found not to possess these genetic changes. Previous research has suggested that fluoroquinolone targets in gram-negative bacteria is DNA gyrase A and within gram-positive bacteria is topoisomerase IV. In vitro mutation studies with anti-gram positive quinolones such as gatifloxacin and sparfloxacin has shown that gyrA is the primary intracellular target in S. pneumoniae. Therefore to ascertain the primary target of moxifloxacin within S. pneumoniae, stepwise selection of four different pneumococcal phenotypes (laboratory strain S. pneumoniae R6, penicillin intermediate and resistant clinical isolates 285 and 158 and pmrA efflux hyperexpresser P1Z1/IN27) were done. In all the in vitro studies, the development of moxifloxacin resistance was through a combination of mutations within the target genes and efflux pump expression. There were two pathways of resistance development where the first started with a Ser83(r)Tyrosine change accompanied by the apparent induction of an efflux pump. This was followed by a Scr79(r)Tyrosine mutation in ParC with the loss of the efflux pump. The second pathway showed no initial change in any of the target genes but was accompanied by the switching on of an efflux pump. No additional mutations were detected in either the parE and gyrB genes. Accumulation assays show that uptake is dramatically reduced in mutants after moxifloxacin challenge in comparison to the respective parent strains.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.649652  DOI: Not available
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