This study investigates the evolution of fluoroquinolone resistance in Burkholderia cepacia and assesses fitness of clinical isolates of the B. cepacia complex. B. cepacia was chosen as a clinically relevant model of antibiotic resistance because these bacteria cause chronic infections in cystic fibrosis patients, are highly resistant to killing by many antimicrobials and consequently require long term antibiotic treatment. Fluoroquinolones are a widely used class of antimicrobials, increasingly used in medical and veterinary practice. A method was optimised and used to determine the rate of mutation occurring in topoisomerase genes that confer resistance to fluoroquinolones. The fitness cost associated with fluoroquinolone resistance mutations was assessed as a measure of the stability of resistance in the bacterial population. Clinical isolates were assessed for hypermutability using mutation to fluoroquinolone resistance as a selective tool. In Gram-negative bacteria resistance to fluoroquinolones occurs via three major mechanisms drug efflux, reduced permeability and target alteration. The spectrum of fluoroquinolone resistance mutations occurring in vitro, the rate at which they arise, and the fitness costs of characterised topoisomerase mutations was investigated, using models relevant to transmission of the Burkholderia cepacia complex. Previous studies have shown that single point mutations in DNA gyrase, conferring resistance, have no or low cost. Only double mutations in gyrA and parC conferred a fitness cost. Second step mutations occur at a faster rate than first step mutations. Mutation in gyrA, therefore, may predispose the genome to mutation in topoisomerase genes.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:499535 |
| Date | January 2008 |
| Creators | Pope, Cassie Francesca |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1445281/ |
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